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Background: Reoperation after breast-conserving surgery (BCS) is common and has been partially associated with the lack of consensus on margin definition. We sought to investigate factors associated with reoperations and variation in reoperation rates across breast surgeons at our cancer center., Methods: Retrospective analyses of patients with clinical stage I-II breast cancer who underwent BCS between January and December 2014 were conducted prior to the recommendation of 'no ink on tumor' margin. Patient demographics and tumor and surgical data were extracted from medical records. A multivariate regression model was used to identify factors associated with reoperation., Results: Overall, 490 patients with stage I (n  = 408) and stage II (n  = 89) breast cancer underwent BCS; seven patients had bilateral breast cancer and underwent bilateral BCS procedures. Median invasive tumor size was 1.1 cm, reoperation rate was 22.9% (n  = 114) and varied among surgeons (range 15-40%), and, in 100 (88%) patients, the second procedure was re-excision, followed by unilateral mastectomy (n  = 7, 6%) and bilateral mastectomy (n  = 7, 6%). Intraoperative margin techniques (global cavity or targeted shaves) were utilized in 50.1% of cases, while no specific margin technique was utilized in 49.9% of cases. Median total specimen size was 65.8 cm 3 (range 24.5-156.0). In the adjusted model, patients with multifocal disease were more likely to undergo reoperation [odds ratio (OR) 5.78, 95% confidence interval (CI) 2.17-15.42]. In addition, two surgeons were found to have significantly higher reoperation rates (OR 6.41, 95% CI 1.94-21.22; OR 3.41, 95% CI 1.07-10.85)., Conclusions: Examination of BCS demonstrated variability in reoperation rates and margin practices among our breast surgeons. Future trials should look at surgeon-specific factors that may predict for reoperations.

Background: Patients referred to comprehensive cancer centers arrive with clinical data requiring review. Radiology consultation for second opinions often generates additional imaging requests; however, the impact of this service on breast cancer management remains unclear. We sought to identify the incidence of additional imaging requests and the effect additional imaging has on patients' ultimate surgical management., Methods: Between November 2013 and March 2014, 153 consecutive patients with breast cancer received second opinion imaging reviews and definitive surgery at our cancer center. We identified the number of additional imaging requests, the number of fulfilled requests, the modality of additional imaging completed, the number of biopsies performed, and the number of patients whose management was altered due to additional imaging results., Results: Of 153 patients, the mean age was 55 years; 98.9% were female; 23.5% (36) had in situ carcinoma (35 DCIS/1 LCIS), and 76.5% (117) had invasive carcinoma. Additional imaging was suggested for 47.7% (73/153) of patients. After multidisciplinary consultation, 65.8% (48/73) of patients underwent additional imaging. Imaging review resulted in biopsy in 43.7% (21/48) of patients and ultimately altered preliminary treatment plans in 37.5% (18/48) of patients (Fig. 1). Changes in management included: conversion to mastectomy or breast conservation, neoadjuvant therapy, additional wire placement, and need for contralateral breast surgery. Fig. 1 Impact of second-opinion imaging reviews on the management of breast cancer patients, Conclusions: Our analysis of second opinion imaging consultation demonstrates the significant value that this service has on breast cancer management. Overall, 11.7% (18/153) of patients who underwent breast surgery had management changes as a consequence of radiologic imaging review.

Few studies have examined care processes within providers' and institutions' control that expedite or delay care. The authors investigated the timeliness of breast cancer care at a comprehensive cancer center, focusing on factors influencing the time from initial consultation to first definitive surgery (FDS). The care of 1,461 women with breast cancer who underwent surgery at Dana-Farber/Brigham and Women's Cancer Center from 2011 to 2013 was studied. The interval between consultation and FDS was calculated to identify variation in timeliness of care based on procedure, provider, and patients' sociodemographic characteristics. Targets of 14 days for lumpectomy and mastectomy and 28 days from mastectomy with immediate reconstruction were set and used to define delay. Mean days between consultation and FDS was 21.6 (range 1-175, sd 15.8) for lumpectomy, 36.7 (5-230, 29.1) for mastectomy, and 37.5 (7-111, 16) for mastectomy with reconstruction. Patients under 40 were less likely to be delayed (OR = 0.56, 95 % CI = 0.33-0.94, p = 0.03). Patients undergoing mastectomy alone (OR = 2.64, 95 % CI = 1.80-3.89, p < 0.0001) and mastectomy with immediate reconstruction (OR = 1.34 95 % CI = 1.00-1.79, p = 0.05) were more likely to be delayed when compared to lumpectomy. Substantial variation in surgical timeliness was identified. This study provides insight into targets for improvement including better coordination with plastic surgery and streamlining pre-operative testing. Cancer centers may consider investing in efforts to measure and improve the timeliness of cancer care.

Purpose: The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC)., Patients and Methods: A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle)., Results: No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption., Conclusion: Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

This study examined the effects of music therapy (MT), immediate and over time, on patients' psychological functioning, quality of life, and physiologic stress arousal. This intervention, whereby patients use music strategies to cope with cancer-related stressors, is based on a transactional stress-coping framework. Using a longitudinal, randomized controlled design, 70 women with metastatic breast cancer received either MT or usual care. The MT consisted of three individual sessions led by a music therapist. Psychological symptoms were measured with the Hospital Anxiety and Depression Scale and quality of life with the Functional Assessment of Cancer Therapy-General plus a a Spirituality subscale at baseline approximately 6 weeks and 3 months later. Visual analog scales, heart rate, and blood pressure were assessed in the MT group immediately before and after individual session. Significant immediate effects of MT were observed: relaxation, p = < .00001; comfort, p = < . 00001; happiness, p = < .00001; heart rate, p = .0003; although no significant differences between conditions were found over time. A high attrition rate underscored the complexities inherent in conducting intervention research with advanced cancer patients.

Purpose: In an open-label trial we have previously demonstrated that paroxetine reduces hot flashes. We initiated a stratified, randomized, double-blind, cross-over, placebo-controlled trial to investigate the efficacy of paroxetine 10 mg and 20 mg compared to placebo in reducing hot flash frequency and composite score. A secondary objective was to evaluate quality of life (QOL) parameters., Patients and Methods: Women who suffered at least two hot flashes a day for 1 month or longer were eligible. Women were randomly assigned to 4 weeks of paroxetine 10 mg or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 mg or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for one week prior to the start of the study and throughout the study, and QOL questionnaires at baseline, week 5 and week 9., Results: 279 women were screened, and 151 were randomly assigned. Paroxetine 10 mg reduced hot flash frequency and composite score by 40.6% and 45.6%, respectively, compared to 13.7% and 13.7% for placebo (P = .0006 and P = .0008, respectively). Paroxetine 20 mg reduced hot flash frequency and composite score by 51.7% and 56.1%, respectively, compared with 26.6% and 28.8% for placebo (P = .002 and P = .004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (P = .01)., Conclusion: Paroxetine is an effective treatment for hot flashes in women with or without a prior breast cancer.

SN biopsy (SNB) has evolved rapidly during the past decade and has now become a standard of surgical care for patients with breast cancer. The primary purpose of SNB is to minimize patient morbidity from axillary staging, but SNB also presents research opportunities to further understand the role of the sentinel node in the natural history of breast cancer. We have attempted to highlight several issues regarding SN and its biopsy in this review, including:(1) Investigation of the optimal particle size for radiotracers. The success of SNB is, in large part, attributed to the particle size of radiolabeled tracers. Electron microscopy demonstrated significant accumulation of the tracer (tin colloid) in harvested SN, of which particle sizes were in the range of 100-150 nm. Therefore, this appeared to be a suitable particle size for SN identification. (2) Invention of a new gamma probe. A cord-and boxless handheld gamma probe was invented, which was more sensitive to radioactivity and involved a background subtraction function based on defined criteria. (3) Characterization of the immunologic response against tumor antigens. Fluorescence-activated cell sorting (FACS) analyses were performed to determine the phenotypic characteristics of B cells and T cells in SN. They revealed an increase in B cells expressing co-stimulated molecules as antigen-presenting cells in SN, compared with non-SN. With respect to T cells, a heterogeneous pattern of naive and memory T cells (TCM) was demonstrated in SN, in contrast to homogeneous pattern with TCM in non-SN. These results may support the concept that B cells play a significant role in antigen presentation required for T cell activation. Studies are currently in progress to test these possibilities.

Background: Women with HER-2 overexpressing metastatic breast carcinoma benefit from trastuzumab-based therapy, but trastuzumab does not cross the blood-brain barrier. The authors characterized central nervous system (CNS) disease in these women., Methods: Using pharmacy records, the authors retrospectively identified 153 women treated with trastuzumab alone or with chemotherapy for HER-2-positive metastatic breast carcinoma at Dana-Farber Partners Cancer Care from June 1998 to December 2000. A study cohort of 122 patients was identified after excluding patients without adequate clinical follow-up or who had CNS disease before trastuzumab treatment. Central nervous system disease was defined as one or more brain metastases or as leptomeningeal carcinomatosis. The median follow-up of this cohort was 23 months., Results: Central nervous system metastases were identified in 34% of patients (95% confidence interval, 26-44%) at a median of 16 months after diagnosis of metastatic breast carcinoma and 6 months from the beginning of trastuzumab therapy. Ninety-three percent of patients with CNS disease presented with clinical symptoms. Five percent of patients with CNS disease had leptomeningeal involvement alone, although 14% had leptomeningeal involvement and parenchymal brain metastases. Fifty percent of patients were responding or had stable disease while receiving trastuzumab at other disease sites at the time of diagnosis of CNS metastasis. The median survival period after CNS metastases was 13 months. Fifty percent of patients died of progressive CNS disease. Patients receiving trastuzumab as first-line therapy for metastatic disease frequently developed brain metastases while responding to or stable on trastuzumab at other disease sites., Conclusions: Metastatic breast carcinoma to the CNS is common among patients receiving trastuzumab-based therapy, including patients responding to therapy outside the CNS. This may be due either to predilection for the CNS by HER-2-positive tumor cells and/or poor penetration of the CNS by trastuzumab or to improved visceral disease control leading to a longer life and onset of late tumor spread to the CNS. Efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted., (Copyright 2003 American Cancer Society.)

Cytotoxic chemotherapy is important for treatment of women with hormone-insensitive or hormone-refractory advanced breast cancer. A variety of agents are effective, alone or in combination. The clinical activity and side effects of many agents, as well as principles for use of chemotherapy, are reviewed. Recent advances in chemotherapy for breast cancer include important studies on the role of dose-intensity, modifications of available agents to reduce side effects, and the availability of oral chemotherapeutics. Finally, the combination of chemotherapy with novel biological agents may improve outcomes for women with certain types of breast cancer. The growing availability of such biological therapies given in combination with chemotherapy may mean better survival in the future for women with advanced breast cancer.

Purpose: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer., Patients and Methods: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy., Results: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity., Conclusion: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

High-dose chemotherapy with autologous stem cell support for the treatment of breast cancer can have a profound effect on patients' quality of life (QOL). This article reviews findings from studies assessing QOL before, during, and after high-dose chemotherapy. The impact of high-dose therapy on overall QOL and specific aspects of QOL including physical functioning, symptoms, psychosocial/emotional and cognitive functioning, sexual functioning, and role functioning is considered. High-dose chemotherapy with stem cell transplant results in largely transient impairment of overall QOL and physical functioning, with subsequent improvement to baseline or better over time. Despite these encouraging global QOL findings, many patients continue to suffer considerable symptoms and concerns attributable to their transplant long after completion of the therapy. Additional research in this area is needed to optimize QOL for patients receiving high-dose chemotherapy.

Purpose: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer., Patients and Methods: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis., Results: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5)., Conclusion: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Three oral 5-fluorouracil (5-FU) therapies have been approved by the US Food and Drug Administration or are in development for the treatment of patients with breast cancer: capecitabine, UFT, and 5-FU/eniluracil. Capecitabine has been approved for breast cancer patients whose disease is paclitaxel-resistant, and either anthracycline-resistant or for whom further anthracycline use is not indicated. A response rate of 20% was observed in an open-label phase II trial of capecitabine in heavily pretreated patients with metastatic breast cancer. Diarrhea and hand-foot syndrome were the most frequently reported toxicities. In a randomized phase II study of capecitabine vs paclitaxel in breast cancer patients who had failed anthracyclines, response rates were 36% for capecitabine vs 21% for paclitaxel. Several phase II trials of 5-FU/eniluracil in breast cancer are ongoing. Preliminary response data from one of these trials on 31 patients with anthracycline- and taxane-resistant advanced breast cancer showed a 16% partial response rate. Grade 3-4 treatment-related toxicities included diarrhea (8%), nausea (3%), and granulocytopenia (3%). In Japan, UFT is widely used for the treatment of breast cancer in both the adjuvant and metastatic settings, though studies in the United States are just getting under way. A phase II trial conducted in Madrid, Spain evaluated the combination of UFT, methotrexate, and leucovorin as salvage therapy for breast cancer patients. The overall response rate was 38% among 21 patients, and diarrhea was the most common toxicity. Many questions remain unanswered about the optimal use of oral 5-FU agents in breast cancer. There seems little question that these agents have substantial activity and will find a place in the therapeutic armamentarium.

A patient with hypertension of sudden onset and with segmental renal ischemia due to an aneurysm in a renal artery branch underwent a nephrectomy which apparently cured his arterial hypertension. The nephrectomy specimen was studied to determine the activity of the juxtaglomerular cells and the concentration of prostaglandins in both ischemic and normal renal tissue. As compared with the normal tissue, the ischemic cortex had an increased number of heavily granulated juxtaglomerular cells. Interstitial fibrosis in the ischemic segment was associated with considerably lower tissue concentration of both prostaglandins A2 and E2 when compared with surrounding normal medulla. These findings appear to correlate well with present theories that consider renal ischemia to be associated with decreased production or response of prostaglandins that normally would counteract the effects of angiotensin.