Background: In 2006, the Institute of Medicine (IOM) issued a report recommending that all cancer survivors receive a customized survivorship care plan (SCP) to increase survivors’ understanding of diagnoses, long-term treatment effects, and ideas for improving overall health. Therefore, the purpose of this study was to compare a tailored SCP program (POST) to treatment as usual (TAU) on patient ratings of quality and content of discussion with providers at the end of their breast cancer treatment.Methods: Two hundred participants were randomized to receive either the POST treatment (n=100) or TAU (n=100) at their last treatment visit. Women were presented with a checklist of 29 survivorship topics and indicated whether their healthcare provider discussed it at their last visit. They were also asked to rate overall quality of discussion (QOD) with their providers and across several QOD subscales.Results: Analyses indicated that on average, POST women endorsed 20 out of the 29 topics compared to 14 topics endorsed by TAU. Additionally, POST women reported a better QOD overall and across all subscales. Conclusion: POST women remembered discussing more survivorship topics and reported better discussions with their providers. As a practical implication, cancer survivors should receive an individualized SCP to ensure that patients feel well informed of their road to survivorship.

We attempted to determine the feasibility of studying prehabilitation exercises to improve shoulder pain and abduction range of motion (ROM) after breast cancer surgery. We evaluated methods of exercise teaching and assessed effect on postsurgical seroma formation. This was a feasibility study with two non-blinded groups of subjects randomized by timing of appointment. This single-site study was performed at an academic tertiary medical center. Sixty cancer patients were randomly assigned to either group 1, in-person teaching arm, n = 36, or group 2, video-only teaching arm, n = 24. Forty-five patients completed the study. Shoulder exercises were assigned to both groups 1 month prior to surgery during evaluation. Group 1 received in-person instruction on exercises, plus an information sheet with exercises and a link to an online video. Group 2 received only the information sheet with exercises and a link to the online video. The primary outcomes considered are as follows: exercise compliance, shoulder pain (via visual analog scale), shoulder abduction ROM (via goniometer), and presence or absence of seroma. Seventy-six percent of study patients chose to exercise. There was no difference in exercise compliance between in-person teaching versus video teaching (75 %, 24/32 vs. 77 %, 10/13, OR = 1.03). Sixty-six of patients (20/30) lost greater than 10° shoulder abduction ROM at 1 month post surgery. Twenty-nine of patients (9/31) had worse shoulder pain than baseline at 1 month post surgery (24 %, 6/25 exercisers, and 50 %, 3/6 non-exercisers). Fifteen percent of patients (4/27) had worse shoulder pain than baseline at 3 months post surgery (8 %, 2/23 exercisers, and 100 %, 2/2 non-exercisers). Prehabilitation exercise program inferred no additional risk of seroma formation (Exercisers 21 %, 7/33 vs. non-exercisers 22 %, 2/9, OR = 0.94). Our subjects were able to perform three exercises independently in the preoperative period. A high-quality randomized controlled trial is necessary to assess the appropriate timing and efficacy of this intervention.

Purpose Early life processes, through influence on fetal stem cells, affect postnatal and adult health outcomes. This study examines the effects of physical activity before and during pregnancy on stem cell counts in umbilical cord blood.Methods We isolated mononuclear cells from umbilical cord blood samples from 373 singleton full-term pregnancies and quantified hematopoietic (CD34(+), CD34(+)CD38(-), and CD34(+) c-kit(+)), endothelial (CD34(+)CD133(+), CD34(+)CD133(+)VEGFR2(+), CD34(+)VEGFR2(+), and CD133(+)VEGFR2(+)), and putative breast (EpCAM(+), EpCAM(+)CD49f(+), EpCAM(+)CD49f(+)CD117(+), CD49f(+)CD24(+), CD24(+)CD29(+), and CD24(+)CD29(+)CD49f(+)) stem/progenitor cell subpopulations by flow cytometry. Information on physical activities before and during pregnancy was obtained from questionnaires. Weekly energy expenditure was estimated based on metabolic equivalent task values.Results Prepregnancy vigorous exercise was associated positively with levels of endothelial CD34(+)CD133(+), CD34(+)CD133(+)VEGFR2(+), CD34(+)VEGFR2(+), and CD133(+)VEGFR2(+) progenitor cell populations (P = 0.02, P = 0.01, P = 0.001, and P = 0.003, respectively); positive associations were observed in samples from the first births and those from the second or later births. Prepregnancy moderate and light exercises and light exercise during the first trimester were not significantly associated with any stem/progenitor cell population. Light exercise during the second trimester was positively associated with CD34(+)VEGFR2(+) endothelial progenitor cells (P = 0.03). In addition, levels of EpCAM(+)CD49f(+) and CD49f(+)CD24(+) breast stem cells were significantly lower among pregnant women who engaged in vigorous/moderate exercise during pregnancy (P = 0.05 and P = 0.02, respectively).Conclusions Vigorous exercise before pregnancy increases the number of endothelial progenitor cells in umbilical cord blood and thus could potentially enhance endothelial function and improve cardiovascular fitness in the offspring. Findings of lower levels of putative breast stem cell subpopulations could have implications on exercise and breast cancer prevention. Prenatal effects of exercise on fetal stem cells warrant further studies.

Women born from a preeclamptic (PE) pregnancy are associated with a lower risk of breast cancer. Prenatal and early-life exposures are hypothesized to influence breast cancer susceptibility through their effect on stem cells. We examined stem cell populations in umbilical cord blood from PE pregnancies and compared with those from pregnancies without this condition. We isolated mononuclear cells from 58 PE and 197 normotensive (non-PE) umbilical cord blood samples and examined the different stem cell populations. Hematopoietic (CD34(+) and CD34(+)CD38(-)), endothelial (CD34(+)CD133(+), CD34(+)VEGFR2(+), CD133(+)VEGFR2(+) and CD34(+)CD133(+)VEGFR2(+)), and putative breast (EpCAM(+), EpCAM(+)CD49f(+), EpCAM(+)CD49f(+)CD117(+), CD49f(+)CD24(+), CD24(+)CD29(+) and CD24(+)CD29(+)CD49f(+)) stem/progenitor cell subpopulations were quantified by flow cytometry and compared between PE and non-PE samples. Hematopoietic CD34(+) cell counts were significantly lowered in PE compared with non-PE samples (P = 0.039, Kruskal-Wallis test). Levels of CD34(+)CD133(+) endothelial progenitor cells were also lower in PE samples (P = 0.032, multiple regression analysis). EpCAM(+) and EpCAM(+)CD49f(+) putative breast stem cell levels were significantly lowered in PE subjects (multiple regression analysis: P = 0.038 and 0.007, respectively). Stratifying by newborn gender, EpCAM(+) and EpCAM(+)CD49f(+) stem cells were significantly lowered in PE samples of female, but not male, newborns. Umbilical cord blood samples from pregnancies complicated by preeclampsia thus had significantly lower levels of hematopoietic, endothelial, and putative breast stem cells than non-PE controls. With a lowered breast cancer risk for offspring of a PE pregnancy, our findings provide support to the hypothesis that susceptibility to breast oncogenesis may be affected by conditions and processes during the prenatal period.

In female survivors who receive supra diaphragmatic irradiation (SDI) for a pediatric malignancy, a serious concern is an elevated risk of breast cancer. The risk approaches 20% at 45 years of age and rivals the risk seen in BRCA mutation carriers. Women treated with SDI have a 37 fold increase in developing breast cancer as compared to the general population. Due to this increased risk, Children’s Oncology Group (COG) developed guidelines recommending screening with MRI and mammography in those women who received SDI between the ages of 10 to 30 years old. This screening should begin 5-8 years following radiation therapy or by 25 years old, whichever comes later. Despite these guidelines being available since 2004, a minority of survivors may be receiving appropriate risk-based care. We sought to identify how many of these patients had received MRI screening and to obtain physician feedback. This is a retrospective analysis looking at tumor registry data from a single institution. Those females treated for a pediatric cancer with involved field SDI were queried. Thirty-one patients ages 10-30 years old were diagnosed with cancer and received SDI from 1984-2008. The providers who were actively following these patients were sent a letter requesting information in regards to MRI screening. Physicians were asked if any screening MRIs were done, if screening will be done in one year’s time, and to provide reasoning to why the study was not completed. Additionally, screening guidelines were provided in each letter prompting physicians to comment on whether the information was helpful. Half of the pediatric female survivors queried were lost to follow-up. Of those women who were followed regularly by their primary provider, less than 10% had MRI breast screening. In addition, half of doctors responded that they would refer the patient for an MRI within the next year. Most physicians felt that the screening information provided was helpful. Some barriers to screening encountered were insurance denial, pregnancy, age less than 25 years old and knowledge about screening. Most women who received SDI for a pediatric cancer are not being evaluated according to the recommended screening despite an elevated risk. This may be secondary to lack of knowledge on the part of both physician and patient. Insurance approval poses another barrier despite the accepted guidelines. These data should prompt radiation oncologists to educate their pediatric patients about risk at the time of therapy. Furthermore, a survivorship plan should be in place so that the transition of care to the primary care provider is seamless. Survivorship programs would ensure screening guidelines are met and women are not lost to follow-up.

Insulin receptor substrate (IRS) 1 and 2 are downstream signaling proteins that influence breast pathophysiology.IRS-1 promotes carcinoma cell proliferation; whereas IRS-2 regulates cell motility, invasion, and glycolysis.Our lab has shown that distinct cellular localization of IRS-2 also plays a role in carcinoma cell function.Oncotype DX (Genomic Health) (ODX) is a 21-gene expression profile used to classify carcinomas with low, intermediate, and high risk recurrence scores (RS).Our aim is to correlate expression and cellular localization of IRS proteins in breast carcinomas with their ODX RS. 97 breast carcinomas sent for ODX testing from 2006-2009 were collected and grouped according to their RS (low, intermediate or high).Immunohistochemistry for IRS-1/-2 was performed.Specific criteria were used to evaluate IRS staining patterns.Follow-up data, ranging from 3-6 years, was available.Statistical analysis was performed to correlate staining patterns of IRS-1/-2 with the three RS groups.IRS-1 staining, predominantly nuclear, did not significantly correlate with RS (P=.5645).IRS-2 expression patterns did show statistical significance amongst the three RS groups (P=.0371).Tumors with intermediate and low RS were more likely to exhibit punctate and diffuse cytoplasmic expression of IRS-2, and cell membrane expression was uncommon in this group.Expression and cellular localization of IRS proteins play an important role in breast cancer cell biology, and expression patterns for IRS-2 do demonstrate a significant correlation with ODX RS.Further studies are required to elucidate the significance of cellular localization of IRS-1/-2 proteins in breast carcinoma cells and their relationship to ODX scores.

Background: At the time of screening mammography, patient data can be collected and entered into a Modified Gail Model Risk Assessment Tool to identify patients at increased risk of invasive breast cancer. In turn, these patients can be referred to high risk centers where risk reduction strategies and chemoprophylaxis can be considered. The objective of this study is to establish how many women are at high risk of invasive breast cancer in a screening population who should be referred to a high risk center for counseling. Methods: This is an observational prospective study evaluating 1,000 women at a single institution presenting for mammographic screening or diagnostic evaluation. At the time of mammography, these women routinely complete a standard intake questionnaire addressing breast cancer risk factors put forward by the institutional clinic. Modified Gail model risk scores were calculated from these data sheets. Women with a 5 year risk of invasive breast cancer of 1.7% or greater were identified as well as women at particularly high risk (≥3.4% or double the 5-year risk). At the time of analysis patients with a history of breast cancer or who underwent diagnostic mammography were excluded. Retrospective data from our institutional high risk clinic from January 2007 to December 2009 was analyzed in respect to patient age at referral, Gail Model Score, personal history of breast cancer, history of benign breast biopsies, and recommendation for and acceptance of chemoprophylaxis. Results: Of 1,000 women screened in the prospective analysis, 366 had ≥1.7% 5-year risk of invasive breast cancer. 26% (96) of these women were under 60 years old while 74% (270) were ≥60 years old. Among the latter group, 19.6% (53) were found to have ≥ 3.4% of developing invasive cancer. In these women with double the 5-year risk, 96.2% had a family history of breast cancer and 69.8% had a prior biopsy. Similarly, in women under 60, greater than half were high risk secondary to a prior biopsy or family history. In the retrospective analysis of 600 patients evaluated in the high risk clinic, 38.8% were eligible for chemoprevention based on age >35, Gail model risk score, and no contraindications to treatment. 45.7% accepted recommendation for chemoprophylaxis as opposed 54.3% who had declined. Age was not found to be a predictor of acceptance of treatment. Conclusions: 1/3 of patients who receive annual screening are at high risk for breast cancer. These patients can be identified from data routinely obtained at the time of screening mammography. These women should be referred for high-risk counseling and consideration of chemoprevention at the time of screening mammography. Further prospective studies may be warranted to determine if this is an effective way to provide risk reduction strategies for high risk women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-04-04.

BACKGROUNDThe size of the breast stem-cell pool could underlie the intrauterine roots of breast cancer. We studied whether breast stem cells exist in umbilical cord blood and if they correlate with hematopoietic stem-cell measurements that have been positively associated with perinatal risk factors for breast cancer.SUBJECTS AND METHODSWe isolated mononuclear cells from umbilical cord blood of 170 singleton full-term pregnancies and determined, by reverse transcription polymerase chain reaction, the presence of genes of putative breast epithelial stem-cell/progenitor markers [including epithelial cell adhesion molecule (EpCAM), CD49f (α6-integrin), CD117 (c-kit receptor), CD24, and CD29 (β1-integrin)]. By immunocytochemistry, we colocalized protein expressions of EpCAM+CD49f+, CD49f+CD24+, and CD24+CD29+. We correlated concentrations of putative breast stem-cell/progenitor subpopulations, quantified by flow cytometry, with concentrations of hematopoietic stem cells.RESULTSMammary stem-cell phenotypes were identified in umbilical cord blood. The measured EpCAM+ subpopulation was positively correlated with concentrations of CD34+ and CD34+CD38- hematopoietic stem cells (both P=0.006). Additionally, EpCAM+CD49f+ and CD49f+CD24+ subpopulations were positively correlated to the CD34+ cells (P=0.03 and 0.008, respectively).CONCLUSIONThe positive association between measurable breast and hematopoietic stem cells in human umbilical cord blood suggests plausible mechanisms for a prenatal influence on breast cancer risk.

IMP3, an oncofetal protein, is a member of the insulin-like growth factor-II (IGF-II) mRNA-binding protein family. Its relevance as a novel biomarker in lung, pancreatic, renal, and cervical adenocarcinoma was recently revealed. However, its role in breast carcinogenesis and tumor progression is not yet established. Basal-like carcinoma was initially identified by gene expression profiling. It accounts for 15% to 30% of all breast cancers. These tumors express basal epithelial markers including cytokeratin 5 but lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), therefore, are often referred to as triple negative breast cancer. They have been found to be associated with a worse overall and disease-free survival. In this retrospective study, we examined the IMP3 expression in invasive ductal carcinoma of the breast and correlated its expression with morphological and biologic prognostic factors. The study group comprised 138 cases of invasive ductal carcinoma retrieved from the surgical pathologic files for a 10-year period from 1997 to 2006. Survival data and clinical stage were available on all 138 patients. Tumor characteristics including size, grade, lymphovascular invasion, necrosis, lymph node metastasis, estrogen receptor, progesterone receptor, and HER2 status were obtained from pathologic reports. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue using mouse monoclonal antibody against IMP3 and CK5/6. Of the 138 breast cancer cases, IMP3 expression was seen in 45 (33%). Twenty-five of the IMP3+ cases were triple negative. We found significant correlation between IMP3 expression and higher grade (P = .001), necrosis (P< .0001) triple negative, and CK5/6 expression (P < .0001 for each). Cox multivariate analysis showed a hazard ratio of IMP3 expression at 3.14 (P = .05). IMP3 is a novel biomarker for triple negative (basal-like) invasive mammary carcinoma, and its expression is associated with a more aggressive phenotype and decreased overall survival.

We examined the relation with birth weight and umbilical cord blood concentrations of haematopoietic stem and progenitor populations in 288 singleton infants. Across the whole range of birth weight, there was a positive relation between birth weight and CD34 + CD38 − cells, with each 500 g increase in birth weight being associated with a 15.5% higher (95% confidence interval: 1.6–31.3%) cell concentration. CD34 + and CD34 + c- kit + cells had J-shaped relations and CFU-GM cells had a U-shaped relation with birth weight. Among newborns with ⩾3000 g birth weights, concentrations of these cells increased with birth weight, while those below 3000 g had higher stem cell concentrations than the reference category of 3000–3499 g. Adjustment for cord blood plasma insulin-like growth factor-1 levels weakened the stem and progenitor cell–birth weight associations. The positive associations between birth weight and stem cell measurements for term newborns with a normal-to-high birth weight support the stem cell burden hypothesis of cancer risk.

22069 Methods: Patients with Estrogen receptor positive, stage I, breast cancer that had Oncotype DX testing done were identified by retrospective review. 10 year relapse risk results obtained with Oncotype DX and Adjuvant Online were compared. The results were separated for T1b and T1c tumors. Cost comparison was done. Results: 30 patients with T1c and 8 patients with T1b disease were identified. All patients were females, age 29–73 years. Her 2 neu receptors were not over expressed in any case. T1c: For T1c tumors, 10 year tamoxifen adjusted relapse rate calculated from Adjuvant Online varied between 10.8–19.2%. Oncotype DX estimated rate of distant recurrence at 10 years in this group varied between 5–25%. 10 year relapse risk results calculated by these two methods were within 5 points of each other in 70% (21/30) cases, between 5–10 points in 23.3% (7/30) cases and > 10 point difference was seen in 6.7% (2/30) cases. Oncotype DX recurrence score identified 50% (15/30) patients in low risk group (Recurrence score < 18 and 10 yr relapse rate < 11), 40% in intermediate risk group (Recurrence score 18 - 30 and 10 yr relapse rate 11–21%), and 10% in high risk group (Recurrence score ≥ 31 and 10 yr relapse rate > 21%). Adjuvant Online results also showed three distinct groups with 26.6% patients in low risk group (10 yr relapse rate 10.8%), 63.3% in intermediate risk group (10 yr relapse rate 15%) and 10% in high risk group (10 yr relapse rate 19.2%). T1b: For T1b tumors, 10 yr relapse rate with Adjuvant Online varied between 9–15.6% and for Oncotype DX it varied between 10–23%. 10 yr relapse risk results calculated by two methods were within 5 points of each other in 62.5% (5/8) cases and difference was >10 points in 37.5% (3/8) cases. Oncotype DX testing assessed higher risk in 87.5% (7/8) cases. Cost Comparison: Oncotype DX cost $3,650 per test and total cost was $138,700. Adjuvant Online cost was 0. Conclusion: There was considerable variability in results of risk assessment provided by Oncotype DX testing and Adjuvant Online. Each method has been validated previously and there is need of a large longitudinal study to compare their risk assessment ability in cost effective fashion. No significant financial relationships to disclose.

It has become important to accurately evaluate the status of HER-2/neu in invasive breast cancer, especially when one is considering the use of anti-HER-2 monoclonal antibody therapy (Trastuzumab). Almost one third of invasive breast carcinomas overexpress the HER-2/neu protein, so the use of the anti-HER-2/neu monoclonal antibody Herceptin (trastuzumab) to block the protein has become important in the management of and in prolonging the survival for patients with metastatic breast cancer. The effectiveness of this therapy is dependent on accurately evaluating the HER-2 status in these tumors, which can be done either by studying the expression of HER-2 protein by immunohistochemistry (IHC) or by evaluating HER-2 gene amplification by fluorescent in situ hybridization (FISH). Since interobserver variability may occur in manually grading HER-2 protein expression by IHC, the aim of this study was to compare the HER-2/neu expression by IHC using a computer-based image analysis system with that of the gene amplification by FISH. Formalin-fixed paraffin-embedded archival tissue from 108 primary infiltrating ductal carcinomas were immunostained using the HercepTest (DAKO). To reduce interobserver variability, membrane staining was evaluated using the Automated Cellular Imaging System (ACIS) by ChromaVision, and the cases were divided into four groups: group 1 (n=23) with HER-2/neu expression ACIS score less than or equal to 1.5; group 2 (n=17) with a score ranging from 1.6 to 1.9; group 3 (n=46) with a score 2.0 to 2.5; and group 4 (n=22) with a score greater than or equal to 2.6. FISH was performed on all of the 108 cases using the PathVysion HER-2/neu DNA probe kit from Vysis Inc. All cases were also manually reviewed and graded as negative, 1+, 2+, and 3+ according to the DAKO HercepTest grading scheme. Cases with negative and 1+immunostaining were considered as HER-2 not overexpressed, and cases with 2+ and 3+ staining were classified as showing HER-2 overexpression. In group 1, 1 of 23 (4%), in group 2, 2 of 17 (12%), in group 3, 5 of 46 (11%), and in group 4, 19 of 22 (86%) cases showed gene amplification by FISH. Furthermore, in group 4 all 15 (100%) cases with an ACIS score of 3 or greater were FISH positive. Correlation with manual IHC score and FISH showed that 2 of the 23 (9%) IHC negative (0 and 1+) cases and 25 of the 85 (29%) IHC positive (2+ and 3+) cases showed gene amplification by FISH. This study shows that the amplification of the HER-2/neu gene correlates better with overexpression of the HER-2/neu protein by IHC when the score is either less than 1.5 or greater than 2.6 by ACIS. Therefore, FISH may be useful to better evaluate HER-2/neu status in breast cancer in cases where the ACIS score by immunohistochemistry is 1.6 to 2.5, and since the correlation is so good, FISH may not be needed for HER-2 evaluation in cases with ACIS scores less than 1.5 and greater than 2.6.