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Objective Breast cancer incidence is rising for women in low and middle income country (LMIC)s. Growing the health care workforce trained in clinical breast exam (CBE) is critical to mitigating breast cancer globally. We developed a CBE simulation training course and determined whether training on a low-fidelity (LF) simulation model results in similar skill acquisition as training on high-fidelity (HF) models in Rwanda. Design A single-center randomized educational crossover trial was implemented. A preintervention baseline exam (exam 1), followed by a lecture series (exam 2), and training sessions with assigned simulation models was implemented (exam 3)—participants then crossed over to their unassigned model (exam 4). The primary outcome of this study determined mean difference in CBE exam scores between HF and LF groups. Secondary outcomes identified any provider level traits and changes in overall scores. Setting The study was implemented at the University Teaching Hospital, Kigali (CHUK) in Rwanda, Africa from July 2014 to March 2015 Participants Medical students, residents in surgery, obstetrics and gynecology, and internal medicine residents participated in a 1-day CBE simulation training course. Results A total of 107 individuals were analyzed in each arm of the study. Mean difference in exam scores between HF and LF models in exam 1 to 4 was not significantly different (exam 1 0.08 standard error (SE) = 0.47, p = 0.42; exam 2 0.86, SE = 0.69, p = 0.16; exam 3 0.03, SE = 0.38, p = 0.66; exam 4 0.10 SE = 0.37, p = 0.29). Overall exam scores improved from pre- to post-intervention. Conclusions Mean difference in exams scores were not significantly different between participants trained with HF versus LF models. LF models can be utilized as cost effective teaching tools for CBE skill acquisition, in resource poor areas.

Background: Breast cancer diagnosis has a number of adverse psychological effects. The Pre-Operative Health and Body (PreHAB) Study tested the impact of exercise and mind-body interventions upon on mood, quality of life, and patient-reported outcomes in women with newly diagnosed breast cancer. Methods: Women with newly diagnosed Stage I-III breast cancer were enrolled through Dana-Farber Cancer Institute and Yale University breast cancer clinics prior to surgery. Participants were randomized 1:1 to an aerobic and strength-training exercise intervention, comprised of twice-weekly meetings with an exercise trainer and home based aerobic exercise, or to a self-directed mind-body relaxation intervention, comprised of a book and CD focused on relaxation and visualization. Participants engaged in the interventions between enrollment and surgery. The EORTC QLQ C-30, Hospital Anxiety and Depression Scale, and Perceived Stress Scale were collected at enrollment and prior to surgery. Results: 49 women were randomized (27 exercise and 22 control). Mean time between enrollment and surgery was 4.2 weeks. At baseline, patients reported moderate levels of anxiety, stress, insomnia, and lack of appetite, as well as diminished emotional and cognitive functioning (Table). Exercise participants significantly increased minutes of weekly exercise vs. mind-body participants (increase of 203 vs. 23 min/wk, p Conclusions: Women with newly diagnosed breast cancer reported a number of physical and psychological symptoms in the pre-operative period. Exercise and mind-body interventions demonstrated promising benefits in improving functioning and reducing symptoms. More work is needed to develop pre-operative programs to help reduce the distress imparted by a cancer diagnosis in the critical time between diagnosis and surgery. Table* Exercise Mind Body Between Groups BaselineChangep valueBaselineChangep valuep valueEmotional Functioning68.6 (23.3)4.7 (18.3)0.2966.3 (24.2)10.0 (20.5)0.050.64Cognitive Functioning79.5 (24.6)-3.3 (24.1)0.6273.8 (22.1)11.7 (15.4)0.0020.03QOL74.0 (15.3)9.7 (15.9)0.00569.0 (21.1)7.5 (18.5)0.110.78Insomnia35.9 (32.6)-16.7 (32.6)0.0334.9 (35.7)-8.3 (21.3)0.060.52Lack of Appetite17.9 (27.0)-13.3 (27.2)0.0311.1 (19.2)-5.0 (22.4)0.530.29Anxiety8.3 (3.4)-0.6 (2.9)0.259.2 (2.5)-1.6 (2.3)0.0060.35Stress14.7 (7.2)-2.2 (4.9)0.0618.4 (5.5)-3.1 (6.8)0.060.77 *Results reported as means (SD). Positive scores on functional and QOL measures indicate improvements; negative scores on symptom measures indicate a decrease in symptoms. Citation Format: Ligibel JA, Giobbie-Hurder A, Dillion D, Shockro L, Campbell N, Rhei E, Troyan S, Dominici L, Golshan M, Chagpar A, Yung R, Freedman R, Tolaney S, Winer E, Frank E, McTiernan A, Irwin M. Impact of pre-operative exercise and mind-body interventions on patient-reported outcomes in women with newly diagnosed breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-02.

BACKGROUND Surgical management of breast cancer in pregnancy (BCP) requires balancing benefits of therapy with potential risks to the developing fetus. Minimal data describe outcomes after mastectomy with immediate breast reconstruction (IR) in pregnant patients. METHODS Retrospective review was performed of patients who underwent IR after mastectomy within a BCP cohort. Parameters included intra- and post-operative complications, short-term maternal/fetal outcomes, surgery duration, and delayed reconstruction in non-IR cohort. RESULTS Of 82 patients with BCP, 29 (35%) had mastectomy during pregnancy: 10 (34%) had IR, 19(66%) did not. All IR utilized tissue expander (TE) placement. Mean gestational age (GA) at IR was 16.2 weeks. Mean surgery duration was 198 min with IR versus 157 min without IR. Those with IR delivered at, or close to, term infants of normal birthweight. No fetal or major obstetrical complications were seen. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 (20%) patients in the IR cohort and 12 (63%) in the non-IR cohort. All patients in the IR cohort successfully transitioned to permanent implant. CONCLUSIONS This report represents one of the largest series describing IR during BCP. IR after mastectomy increased surgery duration, but was not associated with adverse obstetrical or fetal outcomes. IR with TE may preserve reconstructive options when PMRT is indicated. J. Surg. Oncol. 2016;114:140-143. © 2016 Wiley Periodicals, Inc.

Stemming from breast density notification legislation in Massachusetts effective 2015, we sought to develop a collaborative evidence-based approach to density notification that could be used by practitioners across the state. Our goal was to develop an evidence-based consensus management algorithm to help patients and health care providers follow best practices to implement a coordinated, evidence-based, cost-effective, sustainable practice and to standardize care in recommendations for supplemental screening. We formed the Massachusetts Breast Risk Education and Assessment Task Force (MA-BREAST) a multi-institutional, multi-disciplinary panel of expert radiologists, surgeons, primary care physicians, and oncologists to develop a collaborative approach to density notification legislation. Using evidence-based data from the Institute for Clinical and Economic Review, the Cochrane review, National Comprehensive Cancer Network guidelines, American Cancer Society recommendations, and American College of Radiology appropriateness criteria, the group collaboratively developed an evidence-based best-practices algorithm. The expert consensus algorithm uses breast density as one element in the risk stratification to determine the need for supplemental screening. Women with dense breasts and otherwise low risk (15% lifetime risk), do not routinely require supplemental screening per the expert consensus. Women of high risk (20% lifetime) should consider supplemental screening MRI in addition to routine mammography regardless of breast density. We report the development of the multi-disciplinary collaborative approach to density notification. We propose a risk stratification algorithm to assess personal level of risk to determine the need for supplemental screening for an individual woman.

Surgical management of breast cancer in pregnancy (BCP) requires balancing benefits of therapy with potential risks to the developing fetus. Minimal data describe outcomes after mastectomy with immediate breast reconstruction (IR) in pregnant patients.Retrospective review was performed of patients who underwent IR after mastectomy within a BCP cohort. Parameters included intra- and post-operative complications, short-term maternal/fetal outcomes, surgery duration, and delayed reconstruction in non-IR cohort.Of 82 patients with BCP, 29 (35%) had mastectomy during pregnancy: 10 (34%) had IR, 19(66%) did not. All IR utilized tissue expander (TE) placement. Mean gestational age (GA) at IR was 16.2 weeks. Mean surgery duration was 198 min with IR versus 157 min without IR. Those with IR delivered at, or close to, term infants of normal birthweight. No fetal or major obstetrical complications were seen. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 (20%) patients in the IR cohort and 12 (63%) in the non-IR cohort. All patients in the IR cohort successfully transitioned to permanent implant.This report represents one of the largest series describing IR during BCP. IR after mastectomy increased surgery duration, but was not associated with adverse obstetrical or fetal outcomes. IR with TE may preserve reconstructive options when PMRT is indicated. J. Surg. Oncol. 2016;114:140-143. © 2016 Wiley Periodicals, Inc.

Background: There has been an increasing prevalence of contralateral prophylactic mastectomy (CPM), particularly among younger women with breast cancer. There has been limited research evaluating patient preference, knowledge and decision-making regarding this issue. Methods: We surveyed women who had bilateral mastectomy who were enrolled in a multicenter, longitudinal cohort study of women diagnosed with breast cancer at age 40 and younger. The CPM survey included 23 items on decision making, knowledge, and satisfaction with CPM. Results: Of the 550 patients enrolled as of November 2010, 157 (28.5%) had bilateral mastectomy, of whom 124 completed the CPM survey (response rate 79%). Women with bilateral breast cancer (3) or bilateral prophylactic (1) indications for surgery were excluded. Median age at diagnosis was 37 years (range 26–40); 26 women (21%) reported having a genetic mutation (21 BRCA1 and 5 BRCA2). Excluding mutation carriers, women estimated that a median of 10 of 100 women (range 0–90) would develop contralateral breast cancer in the 5 years after unilateral breast cancer treatment and that 5 of 100 women (range 0 — 98) treated with CPM would develop contralateral breast cancer. Eighteen percent of all respondents believed that women who undergo bilateral mastectomy live longer. Women were asked the importance of potential reasons for undergoing CPM (see Table 1). Eighty-two percent of women were “extremely confident” in their decision to undergo CPM and 92% would “definitely” still choose CPM. Conclusion: Young women with breast cancer have high rates of CPM. Many young women who have undergone CPM overestimate the risk of contralateral disease and the benefits of CPM, including believing that CPM will prevent metastasis and extend life. Interventions to counsel young women with early breast cancer to help them make optimal surgical treatment decisions are needed. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-10.

Background: The need for radiation therapy (RT) in conservatively managed DCIS is a source of ongoing debate. This is an updated analysis of a phase II prospective study of wide excision alone for DCIS. The study was activated in May 1995 and closed in July 2002 following accrual of 158 patients because the number of local recurrences (LR) met the predetermined stopping rules. The objective of the analysis is to update the distribution and cumulative incidence of events (LR, contralateral breast cancer [CBC], second malignancy and death from other causes). Materials and Methods: A total of 158 patients had DCIS with predominant nuclear grade 1 or 2, a mammographic extent of ≥2.5 cm, and excision with final microscopic margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The results presented are from the 8-year analysis (8-year minimum potential follow-up time). Twenty-six patients without recurrence who were followed less than 8 years were excluded from the analysis as were 7 first events (4 LR) that occurred beyond 8 years of follow-up; the analysis thus includes 132 patients and 36 first events. Cumulative incidence curves were generated to assess the rates of LR or other events. Median follow up time was 10 years. Results: Overall, 36/132 patients (27%) had a first event as of April 2010. Of these 36 events, 19 were LR, 13 were CBC, 1 was a second malignancy, and 3 were deaths from other causes. Of the 19 LR, 13 (68%) were DCIS only and 6 (32%) were invasive. Fourteen occurred in the same quadrant and 5 were elsewhere in the ipsilateral breast. The 8-year estimated cumulative incidence of LR was 14.4% (95% CI: 8.4-20.4%). For all other events, the 8-year estimated cumulative incidence was 12.9% (95% CI: 3.6-13.1%). The estimated annual percentage rates of LR, CBC, and other events were 2.1%, 1.5% and 0.4%, respectively. Discussion: The results of this prospective study demonstrate a substantial and ongoing risk of LR and CBC in patients with small, nuclear grade 1 or 2 DCIS treated with wide excision with margins of ≥1cm in the absence of RT. Most LRs occurred in the same quadrant, rather than elsewhere in the breast, suggesting that excision alone is inadequate even for this highly selected population. Further study is warranted to determine if there is a subgroup of DCIS patients with nuclear grade 1 or 2 disease who are at low enough risk of LR following wide excision that RT can be omitted safely. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-03.

Background. Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (bev) in the neoadjuvant setting. We sought to explore the safety of neoadjuvant cisplatin/bev in a protocol for triple negative breast cancer (TNBC). Materials and Methods. A total of 51 patients with confirmed TNBC were enrolled in a single-arm trial of neoadjuvant cisplatin plus bev. Of the 51 patients, 28 with confirmed TNBC were enrolled in our trial of single-agent neoadjuvant cisplatin. Two-sided Fisher exact test were used for comparing the 2 trials. Results. The 51 patients received neoadjuvant protocol therapy with cisplatin/bev and underwent definitive local therapy. Breast conserving therapy (BCT) was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 patients (43%); 4 (8%) required explanation of expanders. Also, 28 patients completed neoadjuvant cisplatin therapy. BCT was performed in 13 (46%) and mastectomy with or without reconstruction in 15 (54%). Postoperative complications were reported in 11 patients (39%). None of the 5 reconstructions were lost. We compared all toxicities between the two trials (P = .81 NS), and wound healing related complications between the two trials (P = .10 NS). Conclusions. Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE imaging system overcomes this major obstacle.Color video was acquired simultaneously, and in real-time, along with two independent channels of NIR fluorescence. Grayscale NIR fluorescence images were converted to visible "pseudo-colors" and overlaid onto the color video image. Yorkshire pigs weighing 35 kg (n = 5) were used for final preclinical validation of the imaging system. A six-patient pilot study was conducted in women undergoing sentinel lymph node (SLN) mapping for breast cancer. Subjects received (99m)Tc-sulfur colloid lymphoscintigraphy. In addition, 12.5 microg of indocyanine green (ICG) diluted in human serum albumin (HSA) was used as an NIR fluorescent lymphatic tracer.The FLARE system permitted facile positioning in the operating room. NIR light did not change the look of the surgical field. Simultaneous pan-lymphatic and SLN mapping was demonstrated in swine using clinically available NIR fluorophores and the dual NIR capabilities of the system. In the pilot clinical trial, a total of nine SLNs were identified by (99m)Tc- lymphoscintigraphy and nine SLNs were identified by NIR fluorescence, although results differed in two patients. No adverse events were encountered.We describe the successful clinical translation of a new NIR fluorescence imaging system for image-guided oncologic surgery.

In the multidisciplinary care model, breast imagers frequently provide second-opinion reviews of imaging studies performed at outside institutions. However, the need for additional imaging and timeliness of obtaining these studies has yet to be established. We sought to evaluate the frequency of additional imaging orders by breast surgeons and to evaluate the impact of this supplementary imaging on timeliness of surgery. We identified 2489 consecutive women with breast cancer who underwent first definitive surgery (FDS) at our comprehensive cancer center between 2011 and 2013. The number of breast-specific imaging studies performed for each patient between initial consultation and FDS was obtained. χ 2 tests were used to quantify the proportion of patients undergoing additional imaging by surgeon. Interval time between initial consultation and additional imaging and/or biopsy was calculated. The delay of additional imaging on time to FDS was assessed by t test. Of 2489 patients, 615 (24.7 %) had at least one additional breast-specific imaging study performed between initial consultation and FDS, with 222 patients undergoing additional biopsies (8.9 %). The proportion of patients receiving imaging tests by breast surgeon ranged from 15 to 39 % (p

Purpose It has been hypothesized that wide excision alone with margins ≥ 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial. Methods Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of ≤ 2.5 cm treated with wide excision with final margins of ≥ 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients. Results In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease. Conclusion Despite margins of ≥ 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.

Objective To develop and implement Project LEAD (leadership, education, and advocacy development), a science course for breast cancer activists. Population Students were breast cancer activists and other consumers, mainly affiliated with advocacy organizations in the United States of America. Setting Project LEAD is offered by the National Breast Cancer Coalition; the course takes place over 5 days and is offered 4 times a year, in various cities in the United States of America. Results The Project LEAD curriculum has developed over 5 years to include lectures, problem-based study groups, case studies, interactive critical appraisal sessions, a seminar by an ‘expert’ scientist, role play, and homework components. A core faculty has been valuable for evaluating and revising the course and has proved necessary to provide consistent high quality teaching. Course evaluations indicated that students gained critical appraisal skills, enhanced their knowledge and developed confidence in selected areas of basic science and epidemiology. Conclusions Project LEAD comprises a unique curriculum for training breast cancer activists in science and critical appraisal. Course evaluations indicate that students gain confidence and skills from the course.

Background: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. Methods: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. Results: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13500 epithelial cells per duct (range, 43-492 000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (

Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve the sentinel lymph node (SLN) procedure by facilitating percutaneous and intraoperative identification of lymphatic channels and SLNs. Previous studies suggested that a dose of 0.62 mg (1.6 mL of 0.5 mM) ICG is optimal for SLN mapping in breast cancer. The aim of this study was to evaluate the diagnostic accuracy of NIR fluorescence for SLN mapping in breast cancer patients when used in conjunction with conventional techniques. Study subjects were 95 breast cancer patients planning to undergo SLN procedure at either the Dana-Farber/Harvard Cancer Center (Boston, MA, USA) or the Leiden University Medical Center (Leiden, the Netherlands) between July 2010 and January 2013. Subjects underwent the standard-of-care SLN procedure at each institution using (99)Technetium-colloid in all subjects and patent blue in 27 (28 %) of the subjects. NIR fluorescence-guided SLN detection was performed using the Mini-FLARE imaging system. SLN identification was successful in 94 of 95 subjects (99 %) using NIR fluorescence imaging or a combination of both NIR fluorescence imaging and radioactive guidance. In 2 of 95 subjects, radioactive guidance was necessary for initial in vivo identification of SLNs. In 1 of 95 subjects, NIR fluorescence was necessary for initial in vivo identification of SLNs. A total of 177 SLNs (mean 1.9, range 1-5) were resected: 100 % NIR fluorescent, 88 % radioactive, and 78 % (of 40 nodes) blue. In 2 of 95 subjects (2.1 %), SLNs-containing macrometastases were found only by NIR fluorescence, and in one patient this led to upstaging to N1. This study demonstrates the safe and accurate application of NIR fluorescence imaging for the identification of SLNs in breast cancer patients, but calls into question what technique should be used as the gold standard in future studies.

Sentinel lymph node biopsy (SNB) in pregnant women with breast cancer is uncommonly pursued given concern for fetal harm. This study evaluated efficacy and safety outcomes in pregnant breast cancer patients undergoing SNB.Patients who underwent SNB while pregnant were identified from a retrospective parent cohort of women diagnosed with breast cancer during pregnancy. Chart review was performed to tabulate patient/tumor characteristics, method/outcome of SNB, and short-term maternal/fetal outcomes.Within a cohort of 81, 47 clinically node-negative patients had surgery while pregnant: 25 (53.2 %) SNB, 20 (42.6 %) upfront axillary lymph node dissection, and 2 (4.3 %) no lymph node surgery. Of SNB patients, 8, 9, and 8 had SNB in the first, second, and third trimesters, respectively. 99 m-Technetium (99-Tc) alone was used in 16 patients, methylene blue dye alone in 7 patients, and 2 patients had unknown mapping method. Mapping was successful in all patients. There were no SNB-associated complications. At a median of 2.5 years from diagnosis, there was one locoregional recurrence, one new primary contralateral tumor, three distant recurrences, and one breast cancer death. Among patients who underwent SNB, there were 25 liveborn infants, of whom 24 were healthy, and 1 had cleft palate (in the setting of other maternal risk factors).SNB in pregnant breast cancer patients appears to be safe and accurate using either methylene blue or 99-Tc. This is one of the largest reported experiences of SNB during pregnancy; however, numbers remain limited. SNB rates in this cohort were lower than in non-pregnant breast cancer patients.

Whether wide excision with margins ≥1 cm is sufficient treatment for small low- or intermediate-grade ductal carcinoma in situ (DCIS) is unclear. This is an updated analysis of a phase II, single-arm, prospective trial testing this hypothesis. A total of 158 patients with low- or intermediate-grade DCIS who underwent wide excision alone (without radiation or tamoxifen) were entered onto the trial from 1995 to 2002. Entry criteria included mammographic extent ≤2.5 cm, predominantly low or intermediate nuclear grade, and excision with final microscopic margins ≥1 cm. Eight-year minimum potential follow-up was required for inclusion in the analysis; the final population comprised 143 patients. Cumulative incidence curves were generated to assess rates of local recurrence (LR) or other events. Median follow-up time was 11 years. Nineteen patients (13 %) had LR as a first event within 8 years. Thirteen LR (68 %) were DCIS only and six (32 %) were invasive. Fourteen (74 %) occurred in the original quadrant. The 10-year estimated cumulative incidence of LR was 15.6 %. The estimated annual percentage rate of LR was 1.9 % per patient-year. With longer follow-up, there remains a substantial and ongoing risk of LR in patients with favorable DCIS treated with wide excision margins without radiation. This information should be useful as patients and clinicians weigh the options of wide excision with and without radiation.

We sought to assess whether a close surgical margin (>0 and

564Background: Women who exercise after breast cancer diagnosis have a lower risk of recurrence and mortality, but the biological mechanisms through which exercise impacts breast cancer are unclear. The Pre-Operative Health and Body (PreHAB) Study was a randomized window of opportunity trial designed to test the impact of exercise on tissue and serum biomarkers in women with early breast cancer. Methods: Inactive women with newly diagnosed Stage I-III breast cancer were enrolled through Dana-Farber Cancer Institute and Yale University prior to surgery. Participants were randomized 1:1 to an exercise intervention or Mind-Body control intervention and participated in the interventions between enrollment and the time of surgery. Tumor tissue and serum were collected at enrollment and surgery. Results: A total of 49 women were randomized (27 exercise and 22 control). At baseline, mean age was 52.6, BMI was 30.2kg/m2 and exercise was 49 min/wk. Mean time between enrollment and surgery was 4.2 weeks. Exercise p...

Objective To measure the reliability of the assessment of mediastinal lymph node size in computed tomographic (CT) scans of the thorax. Design Observer agreement study in which radiologists, blinded to one anothers' interpretation, were randomized to read 30 scans each. Population Sixty scans from patients with apparently operable non-small cell carcinoma of the lung were read by radiologists responsible for clinical interpretation (clinical radiologists) and four radiologists with a special interest in thoracic CT (study radiologists). Measurements Radiologists measured the size of left and right superior mediastinal nodes, aortic nodes, and the subcarinal nodes and, on the basis of whether any nodes accessible to mediastinoscopy were greater than 1 cm, recommended whether mediastinoscopy be undertaken. Agreement was quantified using kappa, a measure of chance-corrected agreement. Results Among all radiologists, agreement on whether there were any nodes larger than 1 cm for right superior mediastinal nodes was 0.68; for left superior mediastinal nodes it was 0.28; for aortic pulmonary nodes it was 0.62; for subcarinal nodes it was 0.58; and for any node greater than 1 cm and accessible to mediastinoscopy it was 0.61. The agreement was very similar when the analysis was restricted to the study radiologists. Conclusion Although the good level of overall agreement suggests that CT provides useful information in the evaluation of mediastinal lymph node size, the disagreement was sufficient that it likely contributes to suboptimal sensitivity and specificity of CT in detecting tumor spread reported in previous studies.

Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1–positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n = 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERα; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploinsufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers. [Cancer Res 2009;69(4):1273–8]

Skin-sparing mastectomy has been advocated as an oncologically safe approach for the management of patients with early-stage breast cancer that minimizes deformity and improves cosmesis through preservation of the skin envelope of the breast. Because chest wall skin is the most frequent site of local failure after mastectomy, concerns have been raised that inadequate skin excision could result in an increased risk of local recurrence. Precise borders of the skin resection have not been well established, and long-term local recurrence rates after skin-sparing mastectomy are not known. The purpose of this study was to evaluate the oncologic safety and aesthetic results for skin-sparing mastectomy and immediate breast reconstruction with a latissimus dorsi myocutaneous flap and saline breast prosthesis. Fifty-one patients with early-stage breast cancer (26 with ductal carcinoma in situ and 25 with invasive carcinoma) undergoing primary mastectomy and immediate reconstruction with a latissimus flap were studied from 1991 through 1994. For 32 consecutive patients, skin-sparing mastectomy was defined as a 5-mm margin of skin designed around the border of the nipple-areolar complex. After the mastectomy, biopsies were obtained from the remaining native skin flap edges. Patients were followed for 44.8 months. Histologic examination of 114 native skin flap biopsy specimens failed to demonstrate breast ducts in the dermis of any of the 32 consecutive patients studied. One of 26 patients with ductal carcinoma in situ had metastases to the skin of the lateral chest wall and back. Four other patients, one with stage I disease and three with stage II-B disease, had recurrent breast carcinoma. The stage I patient had a local recurrence in the subcutaneous tissues near the mastectomy specimen. Two patients suffered axillary relapse, and one had distant metastases to the spine. The findings of this study support the technique of skin-sparing mastectomy as an oncologically safe one, based on an absence of breast ductal epithelium at the margins of the native skin flaps and a local recurrence rate of 2 percent after 45 months of follow-up. Although these results need to be confirmed with greater numbers of patients and longer follow-up, skin-sparing mastectomy and immediate breast reconstruction may be considered an excellent alternative treatment to breast conservation for patients with ductal carcinoma in situ and early-stage invasive breast cancer.

Purpose: To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. Methods and Materials: Between 1988 and 1993, 986 evaluable women with clinical Stage I or H invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had Tl tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three"patients (3%) have been lost to follow-up after 20-32 months. Results: No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. Conclusion: Among a group of 92 patients with early-stage breast cancer (typically Tl and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted. © 1997 Elsevier Science Inc. Breast neoplasms, Regional nodal failure, Radiotherapy, Axillary dissection.

Chinese translationRates of contralateral prophylactic mastectomy (CPM) have increased dramatically, particularly among younger women with breast cancer, but little is known about how women approach the decision to have CPM.To examine preferences, knowledge, decision making, and experiences of young women with breast cancer who choose CPM.Cross-sectional survey.8 academic and community medical centers that enrolled 550 women diagnosed with breast cancer at age 40 years or younger between November 2006 and November 2010.123 women without known bilateral breast cancer who reported having bilateral mastectomy.A 1-time, 23-item survey that included items related to decision making, knowledge, risk perception, and breast cancer worry.Most women indicated that desires to decrease their risk for contralateral breast cancer (98%) and improve survival (94%) were extremely or very important factors in their decision to have CPM. However, only 18% indicated that women with breast cancer who undergo CPM live longer than those who do not. BRCA1 or BRCA2 mutation carriers more accurately perceived their risk for contralateral breast cancer, whereas women without a known mutation substantially overestimated this risk.The survey, which was administered a median of 2 years after surgery, was not validated, and some questions might have been misinterpreted by respondents or subject to recall bias. Generalizability of the findings might be limited.Despite knowing that CPM does not clearly improve survival, women who have the procedure do so, in part, to extend their lives. Many women overestimate their actual risk for cancer in the unaffected breast. Interventions aimed at improving risk communication in an effort to promote evidence-based decision making are warranted.Susan G. Komen for the Cure.

1117 Background: SNB in PABC is not often pursued due to concerns for potential fetal harm. There are only limited data available regarding the safety and efficacy of SNB in patients (pts) with PABC. Methods: Pts with PABC who underwent SNB were identified from within an existing multi-institutional PABC cohort diagnosed 1996-2013. Factors evaluated included method and result of SNB evaluation, maternal disease outcome, and fetal outcomes. Results: Within a cohort of 78 PABC pts, 53 had breast surgery while pregnant; 23 (43%) underwent SNB, 27 (51%) underwent initial axillary node (AN) dissection, 18 of whom were clinically node negative, and 3 had no nodal evaluation. Of SNB pts, 21 (91%) had stage 1-2 disease; 14 (61%) had ER/PR+ disease and 7 (30%) HER2+. Eight (35%), 9 (39%), and 6 (26%) women had SNB in the first, second, and third trimesters, respectively. 99-Technetium-labelled sulfur colloid (99-Tc) alone was used for SNB in 14 pts; methylene blue (MB) dye alone was used in 7. SN was identified in 100% of pts; see Table. There were no SNB-associated complications. At a median of 2.4 years from diagnosis, there were no locoregional recurrences, 3 (13%) distant recurrences, and 1 (4%) death from breast cancer. Among pts who underwent SNB, there were 20 liveborn infants and 3 pregnancies ongoing. Of the 20 infants born, 18 were healthy, 1 unknown, and 1 had cleft palate (in setting of maternal risk factors including smoking and methadone). Conclusions: SNB in PABC appears to be a safe and accurate procedure using either 99-Tc or MB techniques. This is one of the largest experiences reported to date of SNB during PABC; however, numbers remain limited and rates of SNB in our cohort were lower than current rates in non-PABC patients. Additional research and monitoring for safety of this procedure is warranted in women with PABC. [Table: see text]

1133 Background: Management of pregnancy-associated breast cancer (PABC) requires balancing benefits of therapy with potential risks to the developing fetus. Surgical management can be influenced by gestational age of fetus and tumor stage. Minimal data describe surgical and obstetrical outcomes after mastectomy with immediate breast reconstruction (IR) in a pregnant patient (pt). Methods: Pts who underwent IR after mastectomy were identified within a multi-institutional PABC cohort. Retrospective chart review was performed for outcomes including adverse intraoperative events, immediate postoperative complications, gestational age at delivery and fetal weight. Other parameters evaluated included stage at presentation, duration of surgery, and use of delayed reconstruction in pts who did not receive IR. Results: Within a cohort of 79 PABC pts, 25 (32%) had mastectomy while pregnant, 8 (32%) of whom had IC; 17 (68%) did not undergo IR. Mean gestational age at time of IR was 16.6 weeks (range 10-30) and all IR utilized tissue expander (TE) placement followed by permanent implant placement in 7 pts. In the IR cohort, 1 (12.5%) pt was stage 0, 3 (37.5%) stage I and 4 (50%) stage IIB. There were no intraoperative or immediate postoperative surgical complications. The mean duration of surgery was 198 min with IR (7 pts) vs. 157 min without IR (available for 12 pts). All women who underwent IR delivered at, or close to, term infants of normal birthweight. One pt had pre-term labor after surgery at 29 weeks which resolved with tocolysis. Mean gestational age at delivery was 37.3 weeks in the IR cohort vs. 36.3 weeks in the non-IR cohort. No fetal abnormalities or major obstetrical complications were seen after IR. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 pts (25%) in the IR cohort and cosmetic outcome was not adversely affected. Conclusions: This report represents one of the largest series describing IR after mastectomy in PABC. Results suggest immediate tissue expander placement after mastectomy may increase duration of surgery but does not lead to adverse obstetrical or fetal outcomes. IR with tissue expanders may preserve reconstructive options when PMRT is indicated.

e11591 Background: Breast cancer surgery is presently performed without real-time image-guidance. We have developed a novel optical imaging system for image-guided surgery that uses invisible near-infrared (NIR) fluorescent light to highlight structures on the surgical field with high sensitivity, specificity, and contrast. We have also performed the first human clinical trial of the imaging system in women undergoing SLN mapping for breast cancer. Methods: We used a portable imaging system with an articulating arm that has 6 degrees of freedom, high power LED light source, custom optics, custom software, and sterile drape. The imaging system provided simultaneous and real-time imaging of color video and NIR fluorescence at up to 15 frames per second. N = 6 women with biopsy- confirmed breast cancer undergoing SLN mapping gave informed consent. All subjects received conventional mapping with Tc-99m sulfur colloid using a handheld gamma probe as well as NIR fluorescence-guided SLN mapping using a mixture of indocyanine green (ICG) diluted to a final concentration of 10 μM in human serum albumin (ICG:HSA). Results: The imaging system was easy to position in the operating room, with the articulating arm providing 50” horizontal reach and 70” vertical reach. Working distance to the patient was 18”. NIR fluorescence excitation was 20 mW/cm2 at 760 nm. NIR-depleted white light was 40,000 lux. A total of 1.6 ml of ICG:HSA was injected intra-tumorally and peri-tumorally and the site massaged for 5 min. 8 of 9 SLNs identified by Tc- 99m sulfur colloid were also identified by NIR fluorescence. However, NIR fluorescence identified an SLN, confirmed to have cancer in it, that was not identified by Tc-99m sulfur colloid. These differences were consistent with asynchrony in the injection techniques. Unlike the gamma-ray probe, NIR fluorescence provided high-resolution, large area optical imaging of the surgical field, and helped guide surgical resection. Conclusions: In this 6-patient pilot study, a novel NIR fluorescence optical imaging system was used for the first time, and provided real-time image-guided surgery for SLN mapping of breast cancer. No significant financial relationships to disclose.

Abstract #1110 Background: The majority of women who develop a BRCA1-related breast cancer develop an ER-/PR-/HER2- breast cancer. Endocrine prophylaxis does not prevent these ER- breast cancers. Therefore, there is a need to develop novel chemoprevention agents in this population. 67% of BRCA1-associated ER- breast cancers also overexpress epidermal growth factor receptor (EGFR). We therefore examined EGFR as a potential target for chemoprevention Methods: We isolated primary mammary epithelial cells (HMECs) from women with a germline BRCA1 mutation who underwent prophylactic mastectomies and from age-matched controls without a mutation who underwent reduction mammoplasties. We used a three-dimensional matrigel-based colony formation assay to assess clonality and proliferative capacity of these cells as well as their response to EGFR-inhibition. Flow cytometry was used to determine the number of EGF binding sites per cell. As a corresponding mouse model we used conditional MMTV-Cre BRCA1-/-p53+/- mice. Results: HMECs from BRCA1 mutation carriers and from controls express EGFR to a similar extent as HCC1937 BRCA1-associated triple-negative breast cancer cells (5x103 binding sites/cell). In ex vivo 3D-cultures we observed that HMECs derived from BRCA1 mutation carriers showed greater clonal and proliferative capacity when compared to normal controls. However while the HMECs derived from BRCA1 mutation carriers and normal controls were equally sensitive to the growth-inhibitory effect of Erlotinib at concentrations as low as 0.2 μM, the ID50 for HCC1937 breast cancer cells was > 10 μM. Similar findings were observed in murine MECs derived from normal control mice as well as BRCA1-/-p53+/- mice which develop breast cancer at the age of 7 to 8 months. Both groups of murine MECs were equally sensitive to Erlotinib growth inhibition. Conclusion: MECs derived from breast tissue of women and mice with a germline BRCA1 mutation express EGFR and are highly sensitive to growth inhibition with the EGFR inhibitor Erlotinib. In contrast, BRCA1-associated HCC 1937 breast cancer cells are more resistant to Erlotinib inhibition despite EGFR expression. We are now studying whether Erlotinib given via oral gavage daily has the potential to delay or prevent breast cancer in this mouse model of BRCA1-related breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1110.

Abstract #4122 Introduction: Statins are safe, reduce cardiovascular risk, and impact pathways critical to cancer progression. We and others have shown lipophilic statins cause apoptosis and growth suppression in vitro and in vivo, and though epidemiologic data are mixed, statin effect appears most evident in estrogen receptor (ER) negative or grade 3 disease. To look for a direct biologic effect of lipophilic statins, we conducted a perioperative pilot window trial in women with breast cancer (BC). Methods: 40 subjects with stage 0,1 BC were randomized to high dose (80mg/day) or low dose (20mg/day) fluvastatin for 3-6 weeks prior to surgery. Paired tissue (core biopsy and surgical specimen), peripheral blood and MRI were obtained. Primary endpoint was Ki-67 (proliferation) change. Secondary endpoints included cleaved caspase-3 (CC3, apoptosis), longest diameter (LD) by MRI, and C-reactive protein (CRP) change. Subgroup analyses was planned by grade (3 vs. 1,2), statin dose; and ER status. Immunohistochemistry (IHC) on paraffin tissue used standard streptavidin biotin methods. A single breast pathologist reviewed all slides; a single radiologist read all MRIs, both blinded to timepoint. Results: Median serum cholesterol decreased by 16% (-23% and -12% for high and low dose, respectively p=0.012), indicating drug effect and compliance. 29 patients had sufficient tumor for paired IHC, 14 and 15 were grade 3 and 1,2, and 10 and 19 were ER - and +, respectively. In grade 3 (73% of which were ER-) vs. 1,2 tumors, there was a significant decrease in Ki-67, -7.2% (interquartile range (IQR) -13.4%, 0% ) vs. -0.3% (IQR -3%, .8%), respectively, p=0.04. CC3 (apoptosis) increased, 60% vs. 13% for grade 3 vs. 1,2 tumors, respectively, p=0.015. ER- and ER+ cases had a similar reduction in Ki67 with a median drop of 2% (IQR -13.4%, 1%) and 1.2% (IQR -6.6%,0.8%), respectively, p=0.56. While CC3 was increased in ER- vs. + (55% vs. 29%), the difference was not statistically significant. There was no dose dependent effect on Ki-67or CC3.There was no evidence of Ki67 or CC3 change when all grades were analyzed together (median drop 1.2%) and no change in CRP. Of 14 subjects with paired MRIs, 4 grade 3 cases showed a significant decrease in LD, marked ductal dilatation and increased necrosis.with statin exposure. Conclusions: A lipophilic statin, fluvastatin, reduced cholesterol and had measurable biologic changes (reduced proliferation, size and increased apoptosis) in stage 0,1 BC after only 3-6 weeks of exposure, specifically in the grade 3 subset. Results support the study of statins for chemoprevention for women at risk for or with stage 0 grade 3 BC, where new agents are needed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4122.

Describes a study designed to evaluate the efficacy of a general information booklet in preparing cancer patients for their first visit to a cancer center. Patients were randomly assigned to receive the booklet in one of three ways: (1) by mail in advance of their appointment (mail group), (2) when they arrived at the center but before their interview (before group), and (3) after their interview (control group). The patients' responses were gathered in a structured interview. Those patients who received the booklet early felt better informed about available services, their physician's reasons for referring them to the center; the mail group felt better informed about their disease and the treatment options and, in general, felt that the center had helped them prepare for their first visit.

Background Near-infrared (NIR) fluorescent sentinel lymph node (SLN) mapping in breast cancer requires optimized imaging systems and lymphatic tracers. Materials and Methods A small, portable version of the FLARE imaging system, termed Mini-FLARE, was developed for capturing color video and two semi-independent channels of NIR fluorescence (700 and 800 nm) in real time. Initial optimization of lymphatic tracer dose was performed using 35-kg Yorkshire pigs and a 6-patient pilot clinical trial. More refined optimization was performed in 24 consecutive breast cancer patients. All patients received the standard of care using 99mTechnetium-nanocolloid and patent blue. In addition, 1.6 ml of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected directly after patent blue at the same location. Patients were allocated to 1 of 8 escalating ICG:HSA concentration groups from 50 to 1000 μM. Results The Mini-FLARE system was positioned easily in the operating room and could be used up to 13 in. from the patient. Mini-FLARE enabled visualization of lymphatic channels and SLNs in all patients. A total of 35 SLNs (mean = 1.45, range 1–3) were detected: 35 radioactive (100%), 30 blue (86%), and 35 NIR fluorescent (100%). Contrast agent quenching at the injection site and dilution within lymphatic channels were major contributors to signal strength of the SLN. Optimal injection dose of ICG:HSA ranged between 400 and 800 μM. No adverse reactions were observed. Conclusions We describe the clinical translation of a new NIR fluorescence imaging system and define the optimal ICG:HSA dose range for SLN mapping in breast cancer. Electronic supplementary material The online version of this article (doi:10.1245/s10434-011-1566-x) contains supplementary material, which is available to authorized users.

Introduction Women who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC. Methods Cultures of MECs were used to examine EGFR protein levels and promoter activity in response to BRCA1 suppression with inhibitory RNA. EGFR was assessed by immunoblot and immunofluorescence analysis, real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR) and flow cytometry. Binding of epidermal growth factor (EGF) to subpopulations of MECs was examined by Scatchard analysis. The responsiveness of MECs to the EGFR inhibitor erlotinib was assessed in vitro in three-dimensional cultures and in vivo. Mouse mammary tumor virus-Cre recombinase (MMTV-Cre) BRCA1flox/flox p53+/- mice were treated daily with erlotinib or vehicle control, and breast cancer-free survival was analyzed using the Kaplan-Meier method. Results Inhibition of BRCA1 in MECs led to upregulation of EGFR with an inverse correlation of BRCA1 with cellular EGFR protein levels (r2 = 0.87) and to an increase in cell surface-expressed EGFR. EGFR upregulation in response to BRCA1 suppression was mediated by transcriptional and posttranslational mechanisms. Aldehyde dehydrogenase 1 (ALDH1)-positive MECs expressed higher levels of EGFR than ALDH1-negative MECs and were expanded two- to threefold in the BRCA1-inhibited MEC population. All MECs were exquisitely sensitive to EGFR inhibition with erlotinib in vitro. EGFR inhibition in MMTV-Cre BRCA1flox/flox p53+/- female mice starting at age 3 months increased disease-free survival from 256 days in the controls to 365 days in the erlotinib-treated cohort. Conclusions We propose that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction. Increased EGFR expression may confer a growth advantage to MECs with loss of BRCA1 at the earliest stages of transformation. Employing EGFR inhibition with erlotinib specifically at this premalignant stage was effective in decreasing the incidence of ER-negative breast tumors in this mouse model.