A Randomized, Double-Blind, Placebo-Controlled Investigation of Selenium Supplementation in Women at Elevated Risk for Breast Cancer: Lessons for Re-Emergent Interest in Selenium and Cancer.

Damage to cellular macromolecules such as DNA and lipid, induced via reactive oxygen species, and indicators of cell proliferation potential such as insulin-like growth factor (IGF) metabolic status are intermediate biomarkers of breast cancer risk. Based on reports that selenium status can affect these markers, a randomized, placebo-controlled, double-blind experiment was conducted to investigate the potential of selenium supplementation to modulate breast cancer risk. Using a placebo tablet or a tablet containing 200 µg selenium provided as high-selenium yeast daily for one year, concentrations of the biomarkers in blood or urine were assessed at baseline and after 6 and 12 months of intervention. The selenium intervention used in this study is presumed to mediate its effect via the induction of glutathione peroxidase activity and the consequential impact of the active form of this protein on oxidative damage. We found no evidence to support this hypothesis or to indicate that systemic IGF metabolic status was affected. Critical knowledge gaps must be addressed for the resurgence of interest in selenium and cancer to garner clinical relevance. Those knowledge gaps include the identification of a specific, high-affinity selenium metabolite and the cellular target(s) to which it binds, and the demonstration that the cellular determinant that the selenium metabolite binds plays a critical role in the initiation, promotion, or progression of a specific type of cancer.

Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. MATERIALS AND METHODS: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. RESULTS: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. CONCLUSION: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. IMPLICATIONS FOR PRACTICE: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer.

BACKGROUND: Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2- metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. PATIENTS AND METHODS: In the present prospective analysis of hormone receptor-positive (HR+)/HER2- and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. CONCLUSION: Ixabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors.

Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage. While intentional weight loss is thought to improve prognosis, its impact on these adipokines is unclear. This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during weight loss. Given the controversies about what dietary pattern is most appropriate for breast cancer control and regulation of adipokine metabolism, the effect of a low fat versus a low carbohydrate pattern was evaluated using a non-randomized, controlled study design. Anthropometric data and fasted plasma were obtained monthly during the six-month weight loss intervention. While leptin was associated with fat mass, adiponectin was not, and the lack of correlation between leptin and adiponectin concentrations throughout weight loss implies independent mechanisms of regulation. The temporal pattern of change in leptin but not adiponectin was affected by magnitude of weight loss. Dietary pattern was without effect on either adipokine. Mechanisms not directly related to dietary pattern, weight loss, or fat mass appear to play dominant roles in the regulation of circulating levels of these adipokines.

Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine.

PURPOSE: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T). EXPERIMENTAL DESIGN: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m(2) on day 1) or AC→XT (X dose: 825 mg/m(2) twice daily, days 1-14; T dose: 75 mg/m(2) on day 1). The primary endpoint was 5-year disease-free survival (DFS). RESULTS: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67-1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51-0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)-positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years. CONCLUSIONS: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients.

Weight loss interventions for breast cancer survivors: impact of dietary pattern.

UNLABELLED: Body weight management is not emphasized in clinical practice guidelines for breast cancer survivors, reflecting the lack of evidence that weight loss improves prognosis. Even if this situation changes, the optimal design for weight loss interventions is unclear. We conducted a 6-month non-randomized, controlled weight loss intervention in 249 post-menopausal breast cancer survivors. This paper reports effects on two secondary endpoints, change in body weight and composition. Participants were predominantly non-Hispanic whites (89%) with a mean age of 54.9 ± 9.2 years, a mean BMI of 29.0 ± 2.6 kg/m: (2) and an average of 43 ± 5% body fat. Two dietary interventions, low fat or low carbohydrate, were investigated and consisted of a 42 day cycle of menus and recipes. Weight loss counseling and anthropometric assessment were provided at monthly clinic visits. One hundred ninety-two women completed the trial (77% retention). In comparison to the nonintervention control, both intervention arms achieved significant decreases in body weight (12.5%), body fat (27.5%), waist circumference (9.5%), and hip circumference (7.8%) (all p < 0.001) with minimal effects on lean mass (1.3% decrease). Median time to 5 and 10% weight loss was 2 (95% confidence interval = 1 to 3) and 4 (95% confidence interval = 3 to 5) months, respectively, and 23% of participants experienced ≥ 15% weight loss. Loss of body weight and fat mass was rapid and substantial irrespective of dietary approach when a structured program was provided with monthly anthropometric assessment and weight loss counseling. TRIAL REGISTRATION: ClinicalTrials.gov NCT01315483.

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND: Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS: This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS: 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION: A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING: Sanofi.

Effect of dietary patterns differing in carbohydrate and fat content on blood lipid and glucose profiles based on weight-loss success of breast-cancer survivors.

INTRODUCTION: Healthy body weight is an important factor for prevention of breast cancer recurrence. Yet, weight loss and weight gain are not currently included in clinical-practice guidelines for posttreatment of breast cancer. The work reported addresses one of the questions that must be considered in recommending weight loss to patients: does it matter what diet plan is used, a question of particular importance because breast cancer treatment can increase risk for cardiovascular disease. METHODS: Women who completed treatment for breast cancer were enrolled in a nonrandomized, controlled study investigating effects of weight loss achieved by using two dietary patterns at the extremes of macronutrient composition, although both diet arms were equivalent in protein: high fat, low carbohydrate versus low fat, high carbohydrate. A nonintervention group served as the control arm; women were assigned to intervention arms based on dietary preferences. During the 6-month weight-loss program, which was menu and recipe defined, participants had monthly clinical visits at which anthropometric data were collected and fasting blood was obtained for safety monitoring for plasma lipid profiles and fasting glucose. Results from 142 participants are reported. RESULTS: Adverse effects on fasting blood lipids or glucose were not observed in either dietary arm. A decrease in fasting glucose was observed with progressive weight loss and was greater in participants who lost more weight, but the effect was not statistically significant, even though it was observed across both diet groups (P = 0.21). Beneficial effects of weight loss on cholesterol (4.7%; P = 0.001), triglycerides (21.8%; P = 0.01), and low-density lipoprotein (LDL) cholesterol (5.8%; P = 0.06) were observed in both groups. For cholesterol (P = 0.07) and LDL cholesterol (P = 0.13), greater reduction trends were seen on the low-fat diet pattern; whereas, for triglycerides (P = 0.01) and high-density lipoprotein (HDL) cholesterol (P = 0.08), a decrease or increase, respectively, was greater on the low-carbohydrate diet pattern. CONCLUSIONS: Because an individual's dietary preferences can affect dietary adherence and weight-loss success, the lack of evidence of a negative effect of dietary pattern on biomarkers associated with cardiovascular risk is an important consideration in the development of breast cancer practice guidelines for physicians who recommend that their patients lose weight. Whether dietary pattern affects biomarkers that predict long-term survival is a primary question in this ongoing clinical trial.

Effect of a low fat versus a low carbohydrate weight loss dietary intervention on biomarkers of long term survival in breast cancer patients ('CHOICE'): study protocol.

BACKGROUND: Weight loss in overweight or obese breast cancer patients is associated with an improved prognosis for long term survival. However, it is not clear whether the macronutrient composition of the chosen weight loss dietary plan imparts further prognostic benefit. A study protocol is presented for a dietary intervention to investigate the effects of weight loss dietary patterns that vary markedly in fat and carbohydrate contents on biomarkers of exposure to metabolic processes that may promote tumorigenesis and that are predictive of long term survival. The study will also determine how much weight must be lost for biomarkers to change in a favorable direction. METHODS/DESIGN: Approximately 370 overweight or obese postmenopausal breast cancer survivors (body mass index: 25.0 to 34.9 kg/m²) will be accrued and assigned to one of two weight loss intervention programs or a non-intervention control group. The dietary intervention is implemented in a free living population to test the two extremes of popular weight loss dietary patterns: a high carbohydrate, low fat diet versus a low carbohydrate, high fat diet. The effects of these dietary patterns on biomarkers for glucose homeostasis, chronic inflammation, cellular oxidation, and steroid sex hormone metabolism will be measured. Participants will attend 3 screening and dietary education visits, and 7 monthly one-on-one dietary counseling and clinical data measurement visits in addition to 5 group visits in the intervention arms. Participants in the control arm will attend two clinical data measurement visits at baseline and 6 months. The primary outcome is high sensitivity C-reactive protein. Secondary outcomes include interleukin-6, tumor necrosis factor-α, insulin-like growth factor-1 (IGF), IGF binding protein-3, 8-isoprostane-F2-alpha, estrone, estradiol, progesterone, sex hormone binding globulin, adiponectin, and leptin. DISCUSSION: While clinical data indicate that excess weight for height is associated with poor prognosis for long term survival, little attention is paid to weight control in the clinical management of breast cancer. This study will provide information that can be used to answer important patient questions about the effects of dietary pattern and magnitude of weight loss on long term survival following breast cancer treatment. CLINICAL TRIAL REGISTRATION: CA125243.

Accelerated partial breast intensity-modulated radiotherapy in women who have prior breast augmentation.

PURPOSE: To examine the outcome of breast cancer patients who have prior breast augmentation treated with lumpectomy followed by accelerated partial breast external intensity-modulated radiotherapy (APBIMRT) with image-guided radiotherapy (IGRT). METHODS AND MATERIALS: Four patients with previous elective subpectoral breast augmentation were enrolled on this APBIMRT trial. These four patients were treated with 10 equal twice daily 3.85 Gy fractions over 5 consecutive days (total dose of 38.5 Gy) using APBIMRT and IGRT. Patients were assessed for pain and cosmetic outcome (physician and a patient self-assessment). RESULTS: At last follow-up, two patients reported an excellent cosmetic results (at 2 years and at 8 months, respectively), one reported good cosmetic results (at 2 years), and one reported poor cosmetic results (at 20 months). Physicians rated the cosmetic outcomes as excellent in two (CEL; at 2 years and 8 months, respectively), good in one (CEL; at 20 months) and excellent in one (KTH; at 2 years). Three patients reported no breast/chest wall pain (two at 2 years and one at 1 year) and the fourth reported mild pain (at 20 months). The mean percent volume of ipsilateral breast receiving 100%, 75%, 50%, and 25% of the prescribed dose was 7.28%, 17.55%, 24.33%, and 33.1%, respectively. The mean breast, planning target volume (PTV), and implant volumes were 399.88 cc, 43.55 cc, and 313.36 cc, respectively. The mean breast prosthesis/total volume (breast tissue plus prosthesis) ratio was 44.55%. The mean PTV/ipsilateral breast and PTV/total volume ratios were 11.1% and 6.1%, respectively. CONCLUSION: The results show that a regimen of APBIMRT with IGRT is possible in patients who have prior breast augmentation.

Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer.

PURPOSE: This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. METHODS: Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 175 mg/m(2) every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m(2) plus paclitaxel 200 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 80 mg/m(2) weekly for 12 weeks. RESULTS: Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC-->P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor-positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. CONCLUSION: The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.

Clinical experience with image-guided radiotherapy in an accelerated partial breast intensity-modulated radiotherapy protocol.

PURPOSE: To explore the feasibility of fiducial markers for the use of image-guided radiotherapy (IGRT) in an accelerated partial breast intensity modulated radiotherapy protocol. METHODS AND MATERIALS: Nineteen patients consented to an institutional review board approved protocol of accelerated partial breast intensity-modulated radiotherapy with fiducial marker placement and treatment with IGRT. Patients (1 patient with bilateral breast cancer; 20 total breasts) underwent ultrasound guided implantation of three 1.2- x 3-mm gold markers placed around the surgical cavity. For each patient, table shifts (inferior/superior, right/left lateral, and anterior/posterior) and minimum, maximum, mean error with standard deviation were recorded for each of the 10 BID treatments. The dose contribution of daily orthogonal films was also examined. RESULTS: All IGRT patients underwent successful marker placement. In all, 200 IGRT treatment sessions were performed. The average vector displacement was 4 mm (range, 2-7 mm). The average superior/inferior shift was 2 mm (range, 0-5 mm), the average lateral shift was 2 mm (range, 1-4 mm), and the average anterior/posterior shift was 3 mm (range, 1 5 mm). CONCLUSIONS: This study shows that the use of IGRT can be successfully used in an accelerated partial breast intensity-modulated radiotherapy protocol. The authors believe that this technique has increased daily treatment accuracy and permitted reduction in the margin added to the clinical target volume to form the planning target volume.

Can telephone counseling post-treatment improve psychosocial outcomes among early stage breast cancer survivors?

OBJECTIVE: To determine whether a telephone counseling program can improve psychosocial outcomes among breast cancer patients post-treatment. METHODS: A randomized trial was conducted involving 21 hospitals and medical centers, with assessments (self-administered questionnaires) at baseline, 12 and 18 months post-enrollment. Eligibility criteria included early stage diagnosis, enrollment during last treatment visit, and the ability to receive the intervention in English. Endpoints included distress (Impact of Event Scale), depression (Center for Epidemiologic Studies Depression Scale), and two study-specific measures: sexual dysfunction and personal growth. The control group (n=152) received a resource directory for breast cancer; the intervention group (n=152) also received a one-year, 16 session telephone counseling program augmented with additional print materials. RESULTS: Significant intervention effects were found for sexual dysfunction at 12 (p=0.03) and 18 months (p=0.04) and personal growth (12 months: p=0.005; 18 months: p=0.03). No differences by group were found in mean scores for distress and depression, with both groups showing significant improvement at 12 and 18 months (all p values for within-group change from baseline were

The addition of hormone therapy to tamoxifen does not prevent hot flashes in women at high risk for developing breast cancer.

Tamoxifen significantly reduces the risk of developing breast cancer in women at increased-risk. The usefulness of tamoxifen has been limited by its side effect profile, especially its propensity to worsen vasomotor symptoms. Hormone therapy (HT) has long been utilized to reduce vasomotor symptoms in peri- and post-menopausal women. The aim of this study was to compare the incidence of hot flashes, weight gain and other side effects associated with taking tamoxifen alone versus tamoxifen in combination with HT in high-risk women. One hundred eighty high-risk women were enrolled into one of two parallel study cohorts to receive tamoxifen alone (93 women) or tamoxifen with HT (87 women). Women were monitored at baseline, 3 months and then yearly for assessments of menopausal symptoms and toxicities associated with tamoxifen alone versus tamoxifen plus HT. We also assessed for differences in menopausal symptoms and toxicities by type of HT (estrogen vs. estrogen and progestin combination). Hot flash scores increased at 3 months and at 1 year compared with baseline in women on tamoxifen alone as well as for women on HT. Women on tamoxifen with estrogen only replacement had the greatest increase in hot flash scores, although this was not significantly different than the increase seen with tamoxifen alone. About 47% of participants on tamoxifen gained weight and there was a strong trend towards less weight gain in women on the combination of tamoxifen and HT, most pronounced for those on tamoxifen with estrogen alone replacement therapy. The addition of HT to tamoxifen therapy does not ameliorate tamoxifen-induced vasomotor symptoms. Tamoxifen associated weight gain, however, may be lessened by the addition of HT.

Predictors for clinical outcomes after accelerated partial breast intensity-modulated radiotherapy.

PURPOSE: To correlate the treatment planning parameters with the clinical outcomes in patients treated with accelerated partial breast intensity-modulated radiotherapy. METHODS AND MATERIALS: A total of 105 patients with Stage I breast cancer were treated between February 2004 and March 2007 in a Phase II prospective trial and had detailed information available on the planning target volume (PTV), ipsilateral breast volume (IBV), PTV/IBV ratio, lung volume, chest wall volume, surgery to radiotherapy interval, follow-up interval, breast pain, and cosmesis. The first 7 of these patients were treated to 34 Gy, and the remaining 98 were treated to 38.5 Gy. All patients were treated twice daily for 5 consecutive days. Univariate and multivariate analyses were performed. RESULTS: The median follow-up was 13 months. No recurrences or deaths were observed. Of the 105 patients, 30 reported mild or moderate breast pain in their most recently recorded follow-up visit. The irradiated lung volume (p < 0.05) and chest wall volume receiving >35 Gy (p < 0.01) were associated with pain. The PTV, but not the PTV/IBV ratio, also correlated with pain (p < 0.01 and p = 0.42, respectively). A total of 72 patients reported excellent, 32 reported good, and 1 reported poor cosmesis. Physician-rated cosmesis reported 90 excellent and 15 good. None of the tested variables correlated with the cosmetic outcomes. CONCLUSION: Radiotherapy to the chest wall (chest wall volume receiving >35 Gy) and to lung correlated with reports of mild pain after accelerated partial breast intensity-modulated radiotherapy. Also, the PTV, but not the PTV/IBV ratio, was predictive of post-treatment reports of pain.

Impact of a commercial reference laboratory test recurrence score on decision making in early-stage breast cancer.

PURPOSE: To investigate whether recurrence score (RS) as determined using a commercial reference laboratory test influences clinicians' treatment recommendations and eventual treatment in patients with early-stage breast cancer. METHODS: A retrospective analysis was performed on 74 patients from a community-based oncology practice with estrogen receptor (ER) -positive, lymph node (LN) -negative stage I or II breast cancer for which RS was obtained. Demographic and pathology information was extracted from medical records. Ten-year relapse-free survival was calculated using Adjuvant! Online. Treatment recommendations before the RS knowledge were compared with treatment recommendations after RS knowledge and to the treatment eventually administered. RESULTS AND CONCLUSION: A weak correlation was found between RS and both patient age and tumor size, modest correlation between RS and tumor grade, and modest correlation between RS and 10-year recurrence as determined by Adjuvant! Online. For 21% and 25% of patients, knowledge of the RS changed the clinicians' treatment recommendations and eventual treatment, respectively. The decision to change from hormone therapy to chemotherapy (with or without hormone therapy) was generally associated with high RS (high distant recurrence risk as determined by the commercial reference laboratory test), whereas the decision to change from chemotherapy to hormone therapy was generally associated with low RS (low distant recurrence risk as determined by the commercial reference laboratory test). Knowledge of the RS changed treatment recommendations and eventual treatment in patients with ER-positive/LN-negative early-stage breast cancer. Use of genomic-based prognosis may result in more accurate estimates of true recurrence risk than currently possible with commonly used prognostic factors (such as patient age, tumor size, and tumor grade) alone and thus lead to an increase in appropriate adjuvant therapy decision making.

Dietary botanical diversity affects the reduction of oxidative biomarkers in women due to high vegetable and fruit intake.

Many health benefits are associated with a high dietary intake of vegetables and fruit (VF); however, little effort has been expended to determine whether the botanical families from which high-VF diets are formulated affect their biological activities. The objective of this study was to determine whether the botanical diversity of high-VF diets alters the response in oxidative biomarkers for lipid peroxidation and DNA oxidation. Two diets were developed that varied in botanical diversity and provided 8-10 servings of VF/d. The high botanical diversity diet (HBD) included foods from the 18 botanical families that induced a reduction in oxidative damage of lipids or DNA. The low botanical diversity diet (LBD) emphasized 5 of these botanical families based on reports that their bioactive components had high antioxidant activity. A total of 106 women completed the study. Participants consumed 9.1 +/- 2.6 and 8.3 +/- 2.1 servings of VF/d with the LBD and HBD diets. Only the HBD diet induced a significant reduction in DNA oxidation (P < 0.05). Both the LBD and the HBD diets were associated with a reduction in lipid peroxidation (P < 0.01). These findings indicate that botanical diversity plays a role in determining the bioactivity of high-VF diets and that smaller amounts of many phytochemicals may have greater beneficial effects than larger amounts of fewer phytochemicals.

8-Isoprostane F2alpha excretion is reduced in women by increased vegetable and fruit intake.

BACKGROUND: Health benefits associated with diets rich in vegetables and fruit (VF) are often attributed to the antioxidant activity of their constituent phytochemicals. However, in vivo evidence that VF actually reduce markers of oxidative stress is limited. OBJECTIVE: An 8-wk dietary intervention was conducted to test the hypothesis that increased VF consumption decreases oxidative stress. Urinary excretion of 8-isoprostane F2alpha (8-iso-PGF2alpha) was used as an index of whole-body lipid peroxidation. DESIGN: The diets evaluated had comparable amounts of all macronutrients but varied in their content of VF. After a 2-wk low-VF (3.0 servings/d) run-in diet, 246 women were randomly assigned to receive either 3.6 (low) or 9.2 (high) servings VF/d. The low-VF group was switched to the high-VF diet during the final 2 wk of the study. Blood and first-void urine specimens were obtained at baseline and at 2-wk intervals thereafter. RESULTS: The run-in diet reduced 8-iso-PGF2alpha concentrations by 33% (P < 0.0001). The excretion of 8-iso-PGF2alpha with the low-VF diet remained the same as that with the run-in diet, whereas urinary concentrations of 8-iso-PGF2alpha were further reduced (P < 0.01) by the high-VF diet, either fed throughout the study or when the diet was switched from low to high VF (P = 0.05). The greatest reductions in 8-iso-PGF2alpha were observed in subjects in the highest quartile of baseline concentrations of 8-iso-PGF2alpha. CONCLUSIONS: A significant reduction in the excretion of 8-iso-PGF2alpha was induced by the run-in diet and the high-VF diet. The degree of reduction was related to the subject's baseline urinary concentration of 8-iso-PGF2alpha.

In vivo investigation of changes in biomarkers of oxidative stress induced by plant food rich diets.

It is well established that vegetables and fruit (VF) contain antioxidant phytochemicals. Consequently, it is expected that individuals who consume diets with a high content of VF should be better protected against oxidative cellular damage than individuals who do not, but not all data support this assumption. The objective of this study was to identify possible explanations for this conundrum. The effects of two diets that differed in VF content on markers of oxidative damage were studied. Sixty-four women participated in a 14-day dietary intervention. Subjects consumed on average either 3.6 or 12.1 servings of VF per day. The primary end points assessed were 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral lymphocyte DNA and 8-isoprostaglandin F-2alpha (8-iso-PGF2alpha) excreted in urine. Subjects consuming the high versus low VF diet had lower concentrations of 8-oxo-dG (p < 0.01) and of 8-iso-PGF2alpha (p < 0.01). However, the reduction in oxidative end points by high VF was not uniform. Rather, an antioxidant effect was observed primarily in individuals whose oxidative end points at baseline were above the median for the study population. Using change in plasma carotenoids (end point minus baseline measurements) as an index of phytochemical intake, the reduction in oxidative markers was inversely proportional to change in plasma carotenoids; this effect was stronger for lipid peroxidation (p < 0.01) than DNA oxidation (p < 0.05). These findings imply that increasing exogenous antioxidant exposure may primarily benefit individuals with elevated levels of oxidative stress. Null findings do not necessarily indicate that an antioxidant compound lacks in vivo activity.

Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28.

PURPOSE: The primary aim of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 was to determine whether four cycles of adjuvant paclitaxel (PTX) after four cycles of adjuvant doxorubicin/cyclophosphamide (AC) will prolong disease-free survival (DFS) and overall survival (OS) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes. PATIENTS AND METHODS: Between August 1995 and May 1998, 3,060 patients were randomly assigned (AC, 1,529; AC followed by PTX [AC --> PTX], 1,531). Patients > or = 50 years and those younger than 50 years with estrogen receptor (ER) or progesterone receptor (PR) -positive tumors also received tamoxifen for 5 years, starting with the first dose of AC. Postlumpectomy radiotherapy was mandated. Postmastectomy or regional radiotherapy was prohibited. Median follow-up is 64.6 months. RESULTS: The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (relative risk [RR], 0.83; 95% CI, 0.72 to 0.95; P = .006). Five-year DFS was 76% +/- 2% for patients randomly assigned to AC --> PTX compared with 72% +/- 2% for those randomly assigned to AC. Improvement in OS was small and not statistically significant (RR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Five-year OS was 85% +/- 2% for both groups. Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction (for DFS, P = .30 and P = .44, respectively). Toxicity with the AC --> PTX regimen was acceptable for the adjuvant setting. CONCLUSION: The addition of PTX to AC resulted in significant improvement in DFS but no significant improvement in OS with acceptable toxicity. No significant interaction between treatment effect and receptor status or tamoxifen administration was observed.