Faculty Bibliography

Estrogen alone cannot explain the differences in breast cancer (BC) recurrence and incidence rates in pre- and postmenopausal women. In this study, we have tested a hypothesis that, in addition to estrogen, both iron deficiency due to menstruation and iron accumulation as a result of menstrual stop play important roles in menopause-related BC outcomes. We first tested this hypothesis in cell culture models mimicking the high-estrogen and low-iron premenopausal condition or the low-estrogen and high-iron postmenopausal condition. Subsequently, we examined this hypothesis in mice that were fed iron-deficient and iron-overloaded diets. We show that estrogen only slightly up-regulates vascular endothelial growth factor (VEGF), an angiogenic factor known to be important in BC recurrence. It is, rather, iron deficiency that significantly promotes VEGF by stabilizing hypoxia-inducible factor-1alpha. Conversely, high iron levels increase oxidative stress and sustain mitogen-activated protein kinase activation, which are mechanisms of known significance in BC development. Taken together, our results suggest, for the first time, that an iron-deficiency-mediated proangiogenic environment could contribute to the high recurrence of BC in young patients, and iron-accumulation-associated pro-oxidant conditions could lead to the high incidence of BC in older women

Measures to prevent breast cancer are receiving particular attention by women at high risk from either clinico-pathologic findings or genetic susceptibility. Life-style and nutritional interventions have been difficult to quantify, but merit further study. Chemoprevention with tamoxifen and subsequently with the related raloxifene demonstrates some efficacy, but may be not be applicable to premenopausal women (with regard to raloxifene), or have low acceptance (with regard to tamoxifen). Based on the importance of the insulin-like growth factor-1 pathway in mammary gland development, and the availability of a potent inhibitor, pilot studies are ongoing to evaluate such an inhibitor in women with demonstrable high risk to develop breast cancer. Short-term interventions with the inhibitor have been completed, and subsequent interventions are planned

Objective: Locally advanced breast cancer (LABC) is the most common presentation of breast cancer worldwide. In the United States, neoadjuvant therapy has become the standard of care for LABC. Recently, Adams et al reported a 34% pathologic response rate among 105 patients with LABC treated with taxanebased, preoperative chemo-radiation: 5-year DFS and OS results were comparable to those of much more aggressive chemotherapy regimens in the neoadjuvant setting. As is reported for patients treated by neoadjuvant chemotherapy, the achievement of a pathological response to chemo-radiation reflected better DFS and OS. Importantly, a pathological response occurred in 54% of patients with hormone-negative tumors. Since this approach is simple and cost-effective, it has attracted interest from several international centers. We report the surgical outcomes after taxane-radiation in 63 LABC patients treated in a multiinstitutional clinical trial in India, South Africa, and the United States. Methods: Women with LABC (stages IIB-IIIC), ECOG performance status of 0 to 1, were eligible. Patients were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 6-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Seventeen of 63 patients received four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 prior to the paclitaxel -RT regimen. Mastectomy or lumpectomy, as decided by each surgeon, was performed 4 weeks after completion of preoperative therapy or upon recovery of chemoradiationinduced dermatitis. All patients had a level I/II axillary lymph node dissection. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. Surgical complications were recorded. Results: Forty-three patients underwent modified radical mastectomyand 20 underwent lumpectomy. Of mastectomy patients, 17 (39.5%) underwent immediate breast reconstruction: free flap reconstruction (8), pedicle flaps (3), advancement flaps(2), tissue expander placement (2), and major chest wall and sternum reconstruction (1). Of lumpectomy patients, five (25%) had further surgery for positive margins; a second lumpectomy (3), and a mastectomy (2). All revealed residual disease and negative margins were achieved. Twenty-one patients had at least 1 complication of whom 17 were treated as outpatients. Eleven (17.4%) had a recurrent seroma, 8 (12.7%) had delayed healing, and 7 (11.1%) developed a postoperative infection. Of the 17 who underwent reconstruction, 3 (17.6%) developed flap necrosis, requiring surgical debridement. The degree of acute chemo-radiation dermatitis was analyzed to explore correlation with the surgical complications. Dermatitis was grade 1 in 21 patients, grade 2 in 29 patients, grade 3 in 11 patients, and 2 had none. The grade of dermatitis did not correlate with risk of complications. Conclusions: Preoperative paclitaxel with radiotherapy is relatively well tolerated. Risk of complication is similar to that reported in the literature for patients treated with neoadjuvant therapy. The highest morbidity was associated with immediate free flap reconstruction. Delayed reconstruction may be advisable for patients treated with neoadjuvant chemo-radiation. (Table presented)

Purpose. The purpose of this study was to compare the surgical and pathological variables which impact rate of re-excision following breast conserving therapy (BCS) with or without concurrent additional margin excision (AM). Methods. The pathology database was queried for all patients with DCIS from January 2004 to September 2008. Pathologic assessment included volume of excision, subtype, size, distance from margin, grade, necrosis, multifocality, calcifications, and ER/PR status. Results. 405 cases were identified and 201 underwent BCS, 151-BCS-AM, and 53-mastectomy. Among the 201 BCS patients, 190 underwent re-excision for close or involved margins. 129 of these were treated with BCS and 61 with BCS-AM (P < .0001). The incidence of residual DCIS in the re-excision specimens was 32% (n = 65) for BCS and 22% (n = 33) for BCS-AM (P < .05). For both the BCS and the BCS-AM cohorts, volume of tissue excised is inversely correlated to the rate of re-excision (P = .0284). Multifocality (P = .0002) and ER status (P = .0382) were also significant predictors for rate of re-excision and variation in surgical technique was insignificant. Conclusions. The rate of positive margins, re-excision, and residual disease was significantly higher in patients with lower volume of excision. The performance of concurrent additional margin excision increases the efficacy of BCS for DCIS.

BACKGROUND: Despite recent advances in breast cancer treatment, breast cancer related lymphedema (BCRL) continues to be a significant problem for many survivors. Some BCRL risk factors may be largely unavoidable, such as mastectomy, axillary lymph node dissection (ALND), or radiation therapy. Potentially avoidable risk factors unrelated to breast cancer treatment include minor upper extremity infections, injury or trauma to the arm, overuse of the limb, and air travel. This study investigates how providing information about BCRL affects the cognitive and symptomatic outcome of breast cancer survivors. METHODS: Data were collected from 136 breast cancer survivors using a Demographic and Medical Information interview instrument, a Lymphedema Education Status interview instrument, a Knowledge Test for cognitive outcome, and the Lymphedema and Breast Cancer Questionnaire for symptom outcome. Data analysis included descriptive statistics, t tests, chi-square (chi(2)) tests, and regression. RESULTS: BCRL information was given to 57% of subjects during treatment. The mean number of lymphedema-related symptoms was 3 symptoms. Patients who received information reported significantly fewer symptoms and scored significantly higher in the knowledge test. After controlling for confounding factors, patient education remains an additional predictor of BCRL outcome. Significantly fewer women who received information about BCRL reported swelling, heaviness, impaired shoulder mobility, seroma formation, and breast swelling. CONCLUSIONS: Breast cancer survivors who received information about BCRL had significantly reduced symptoms and increased knowledge about BCRL. In clinical practice, breast cancer survivors should be engaged in supportive dialogues so they can be educated about ways to reduce their risk of developing BCRL.