bluuebunny/crossref_metadata_2025 huggingface dataset:
Lapatinib selectively inhibits HER2 over-expressing breast cancer stem-like cells.
Authors: Johnson RL , Farnie G , Clarke RB , Bundred NJ
Published: December 2010

Abstract #5052

Introduction  Standard drug treatment kills proliferating cells but recent studies show the tumourigenic cancer stem cells (CSC) are not affected, leading to recurrence. HER2 over-expression in Ductal Carcinoma In Situ (DCIS) and invasive cancer is associated with poor prognosis. We determined the effect of a dual tyrosine kinase inhibitor (Lapatinib) on CSC growth in mammosphere (non-adherent) and 3D culture in HER2 over-expressing cell lines and primary DCIS samples.  Methods  MCF7, BT474 (HER2+), DCIS.com and SUM225 (HER2+) cell lines were cultured as mammospheres in the presence or absence of Lapatinib (0.1-5mM). FACS analysis was used to measure proliferation (Ki67) and apoptosis (annexin / PI) rates. Western blotting was used to analyse levels phosphorylated MAPk and AKT in mammospheres. 3D matrigel culture of cell lines and primary DCIS cells was carried out with and without Lapatinib (1mM), the size and number of colonies grown were assessed. Statistical analysis was by unpaired 2-tailed T test.  Results  Mammosphere forming efficiency (MFE) of HER2 over-expressing but not HER2 negative cell lines was inhibited by Lapatinib (at IC50 p<0.05) and the IC50 for inhibited cell lines determined (Table 1). Lapatinib treatment at the IC50 concentration in both BT474 and SUM225 reduced proliferation by 10% after 24 hours of mammosphere culture (p<0.05), however there were no differences in apoptosis. Lapatinib reduced pMAPk and pAKT in HER2 over-expressing cells during mammosphere culture in a dose dependent manner. Secondary mammosphere culture demonstrated a sustained 50% reduction in mammosphere formation from primary mammospheres cultured with Lapatinib, suggesting self renewal was inhibited in mammosphere culture.  In 3D culture of HER2 over-expressing SUM225 and primary DCIS samples Lapatinib (1µM) significantly reduced the size of the colonies but no difference was observed in the number of colonies formed (Table 1).    Conclusion  Lapatinib selectively inhibits breast cancer stem cell activity by reducing proliferation in HER2 over-expressing lines measured using non-adherent and 3D culture. These findings need to be verified by an in vivo limiting dilution tumourgenicity assay.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5052.
The effect of intermittent versus continuous energy restriction on biomarkers of breast cancer risk.
Authors: Harvie M , Chapman M , Cuzick J , Flyvbjerg A , Jebb S , Mattson M , Howell A
Published: December 2010

Abstract #506

Excess energy, whether it is the form of high energy diets or low energy expenditure (sedentary lifestyle), is a risk factor for breast cancer. Observational studies show that continuous energy restriction (CER) and exercise reduce risk, particularly of postmenopausal breast cancer. Animal data indicate that intermittent energy restriction (IER) may be superior or at least as effective as continuous energy restriction in preventing or reducing the growth rate of mammary tumours. IER may also be more acceptable than CER which has been difficult to implement.  We have tested the effectiveness and acceptability of IER and have performed a randomised trial of IER (n=53) versus CER (n=54) in overweight or obese premenopausal women. Energy restriction was 25% in both arms. IER subjects had approximately 550 kcal on 2 days per week and add lib food on other days; CER subjects had approximately 1500 kcal / day over 7 days. Nineteen women (18 %) withdrew from the study before 6 months (IER = 12, CER = 7, main reasons: stress = 4, pregnancy = 3, change in employment = 3, couldn't stick to diet = 3).  Change in weight and biomarkers for last observation carried forward are reported.  At 6 months. Both IER and CER are effective for loss of weight -7.9 vs. - 6.7% P = 0.26 and waist circumference -6.3 vs. -5% P = 0.13, and for lowering serum levels of leptin -43.3 vs. -39.8% P = 0.53; C – reactive protein -14.8 vs.-20.3% P = 0.15 and free androgen index -9.8 vs.-14.4% P = 0.90. Both IER and CER increased circulating levels of sex hormone binding globulin + 18.1 vs. 10.8% P = 0.51, and plasma adiponectin +11 vs. +1% P = 0.09. IER is better at lowering insulin resistance at 6 months than CER -29.6 vs. -15.3 % P <0.05.  These data indicate that 2 days IER gives similar results to CER with respect to weight loss and many of the risk parameters measured and may be an alternative approach to continuous energy restriction. The superior reductions in insulin resistance with IER which may be related to periods of very low calorie intake (approximately 70% restriction). We are waiting data of the effects of IER vs. CER on the IGF-1 axis and oxidative stress. Future studies will investigate the mechanism of IER, its optimal duration and its influence on mammary cell function.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 506.
Hyperoxic respiratory challenges to monitor chemotherapy effects on Brca1/p53 deficient mice breast tumors.
Authors: Kim JG , Kim Y , Cerussi AE , Lee EY , Tromberg BJ
Published: December 2010

Abstract #5065

Background: Response to cancer treatments such as radiotherapy, chemotherapy, and photodynamic therapy are less effective when tumors are hypoxic. Hyperoxic gas intervention has been shown to improve tumor oxygenation. Here we report how hemodynamic changes due to oxygen intervention are related to the tumor response during cisplatin treatment of spontaneous mammary tumors developed in mice with conditional inactivation of the Brca1 and p53 genes.  Materials and Methods: We treated mammary tumors in Brca1/p53 knockout mice (n=8) with 1.2mg/kg of Cisplatin (i. p. daily for a week), and tumor volume and body weight were monitored during treatment. We imaged tumors during chemotherapy using an optical imaging system that quantifies intrinsic light scattering and absorption by projecting spatially modulated, near infrared (NIR) light (650nm to 980nm) onto tissues and calculating oxy-(Ohb), deoxy-(RHb), total hemoglobin (THb) concentrations, tissue oxygen saturation (StO2) values, and scattering values at all wavelengths. During imaging, animals were anesthetized using 1.5% isoflurane and each animal inhaled medical air (33% O2) for 6 min followed by 100% oxygen for an additional 12 min.  Results: Among 8 tumors, 5 (volume=0.38±0.1) showed response to Cisplatin treatment while the other 3 tumors (volume=0.56±0.12) did not. Tumors responding to Cisplatin displayed greater than 2-fold increase in [Ohb] and [RHb] during oxygen intervention compared to non responding tumors (p<0.05). (Fig.1) Significant differences in tumor size changes (data not shown) were also observed between responders and non-responders.    Discussion: Breast cancers are heterogeneous in their molecular profiles as well as treatment response. Hyperoxic gas intervention during chemotherapy combined with intrinsic signal optical imaging can be used to evaluate vascular reactivity. Our preliminary results indicate that OHb and RHb reactive tumors are significantly more likely to respond to Cisplatin chemotherapy. This general approach can be extended to other tumor therapy models and can be readily translated to patients.  Keywords:Breast Cancer, Brca1/p53 Transgenic Mice, Diffuse Optical Imaging, Cisplatin Chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5065.
αB-crystallin, vimentin and increased p53 expression levels in breast cancer is associated with poor prognosis.
Authors: Quinlan PR , Sreseli R , Quinlan RA , Hadad S , Bray SE , Kernohan N , Kellock D , Baker L , Purdie C , Jordan L , Thompson AM
Published: December 2010

Abstract #5070

Background: Previous studies have identified αB-crystallin as a marker of poor prognosis for breast cancer and have suggested that it is an excellent marker for tumours of basal origin. Increased expression of αB-crystallin has been associated with anchorage-independent growth and metastasis leading to the suggestion that αB-crystallin is an oncoprotein. We have considered whether the αB-crystallin binding proteins, vimentin and HSP27 also show a similar association with poor prognosis. We also investigated whether either HSP27 phosphorylation HSP27 or p53 expression could be associated with αB-crystallin expression.  Methods: Tissue Micro Arrays of 0.6x0.6mm cores of 205 breast cancers were stained with antibodies to αB-crystallin, vimentin, p53 (antibodies DO1, FP3), HSP27 (antibody ERD5) and HSP27 82P. The levels of protein expressions were then compared with clinical and pathological parameters.  Results: The expression of αB-crystallin was positively associated with vimentin (P<0.001 Fisher's exact test (FET)). We have confirmed that αB-crystallin expression is linked to a low expression of the estrogen receptor and reduced survival (P<0.001 (FET), P=0.002 Kaplan Meier Log Rank (KM) respectively). Vimentin expression was similarly associated with estrogen receptor (ER) negative cancers and poor survival (P <0.001 (FET), P= 0.002 (KM Log Rank) respectively). Low expression of HSP27 resulted in poor three-year survival (P=0.007 (KM Log Rank)), but longer-term survival was unaffected (P=0.09 (KM Log Rank)). In contrast to αB-crystallin, low expression of HSP27 was associated with ER and progesterone receptor (PGR) negativity (P<0.001 (FET), P=0.001 (FET)). HSP27 82P similarly resulted in poor three-year survival (P=0.01 (KM Log Rank)) compared with longer-term survival (P=0.05 (KM Log Rank)). In samples positive for either αB-crystallin or vimentin, a strong association with increased p53 expression (p53 antibodies: DO1(P<0.001 (FET)) and FP3(P<0.001 (FET))) was found.  Conclusions: The increased expression of the protein chaperone, αB-crystallin was linked with reduced survival as well as it's binding partner, vimentin. We found that within this patient subgroup, there was an increased level of p53. The potential functional significance of this interaction for metastasis will be discussed in the context of other predictive markers for breast cancer. A similar association was not found for HSP27 expression.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5070.
Evaluation of bcl-2 protein expression in the normal mammary epithelium of premenopausal women treated with raloxifene.
Authors: Lopes IM , da Silva BB , dos Santos AR , Lopes-Costa PV
Published: December 2010

Abstract #5087

Background: Bcl-2 is one of the most important blockers of cell death and therapeutic strategies to reduce its expression may be useful in breast cancer chemoprevention. The aim of this study was to evaluate the expression of the bcl-2 protein in the normal breast tissue of premenopausal women. Materials and Methods: Thirty ovulatory premenopausal women of 18 to 40 years of age, who had been diagnosed fibroadenoma of the breast participated of this study. This was a randomized, double-blind, placebo controlled study. Patiens were randomized into two groups: Group A (placebo, n=16) and Group B (raloxifene, n=14). The drug was administered in the dose of 60 mg/day for 22 days, beginning on the first day of menstrual cycle. Excision of fibroadenoma was carried out on the 23rd day during which a sample of normal breast tissue was collected for immunohistochemistry. Cells in which cytoplasm was intensely stained in brown by anti-bcl-2 antibody were considered positive for bcl-2. A number of 500 cells on each slide were counted using a light microscope (400x), beginning with the area in which there was the greatest expression of bcl-2. The percentage of stained cells for each case was obtained from the ratio between the number of cells with stained cytoplasm and total of cells multiplied by 100. Student's t test was used to compare the means of percentages of stained cytoplasms in the two groups (p<0.05). Results: There was a significant reduction in the mean percentage of bcl-2-stained cytoplasms in the group that received raloxifene compared to the placebo group, 10.90±2.11 and 19.05±2.36, respectively (p<0.017). Discussion: Our results indicate that raloxifene reduces the anti-apoptotic bcl-2 protein expression in the normal breast tissue of premenopausal women reinforcing the argument for its use in chemoprevention of breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5087.
The future of breast cancer research and practice in Asia, Latin America, and the Middle East/North Africa: a qualitative horizon scanning analysis.
Authors: Bridges JF , Coates A , Piccart MJ , Barrios CH , Trudeau M , Huang C , Kim S , Wu J , Saip P , Buchanan D
Published: December 2010

Abstract #5095

Objective: To conduct a horizon-scanning analysis to identify future needs, challenges and trends relating to breast cancer research and practices globally with special emphasis on emerging and understudied regions.  Methods: Following the design and pilot of the survey instrument, data was derived from key informant interviews with 221 thought leaders in breast cancer in Asia (n=97), Latin America (n=46), Middle East/North Africa (n=39) and Australia and Canada (n=39). Thought leaders were identified using a combination of purposive and snowballing sampling and included oncologists, surgeons, other breast cancer specialists, advocacy leaders and policy makers. Transcripts and field notes were then coded and compared, and a taxonomy of 20 issues was developed. The propensity of these themes were then analyzed and compared across the four regions.  Results: In Asia the most prevalent issues were i) building capacity for clinical research, ii) more nurses for patient care/education, iii) keeping up to date with new information and iv) increased targeted/personalized treatment. In Latin America key themes were the need to i) increase targeted/personalized treatment, ii) address disparities among the underserved, iii) high cost to third party payers, iv) increase capacity for clinical research and v) control out of pocket costs for patients. In the Middle East/North Africa key themes were the need for i) building capacity for clinical research, ii) more nurses for patient care/education, iii) increased public education on screening and iv) increased capacity for early detection. In Australia and Canada issues were i) keeping up to date with new information, ii) weighing the cost effectiveness of new treatments, iii) the need for increased data sharing and iv) improving communication between stakeholders.  Discussion: While a number of respondents expressed observations relating to country specific etiology of disease (such as women presenting at younger ages and with more aggressive tumors) the lack of national registries and local clinical/genetic research make it hard to confirm these anecdotes scientifically. Finally, increased focus on the development of effective advocacy and policy leadership are needed in these regions to draw attention and resources towards issues of community empowerment, survivorship and quality of life which were neglected by all but a handful of respondents.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5095.
Patient perception of choice in decision-making for early-stage breast cancer: do race and socioeconomic status matter?.
Authors: Dhage S , Fei K , Weidman J , Guth AA , Bickell N
Published: December 2010

Abstract #5098

Background: It has been well-established that survival following breast conservation surgery(BCS) vs. mastectomy(MT) is equivalent. Therefore women with early-stage breast cancer should given a choice between BCS and MT. It has recently been recognized that women who have a choice of surgery type have better short term health status. Some studies suggest that there is treatment variation according to socioeconomic status and race. But little is known about whether there is a variance in a feeling of choice based on ethnicity/race and socioeconomic status. Do these factors affect women's sense of choice in her surgical treatment?  Methods: Women with a newly diagnosed Stage I/II breast cancer were identified from pathology databases of 6 participating NYC hospitals, including 3 municipal, 2 tertiary, and one community hospital. Patients were surveyed an average of 6 months after surgical treatment. Bivariate, logistic and factor analyses were conducted on the 258 participants. IRB approval was obtained at all 6 institutions.  Results: Despite high rates(88%) of reported discussion of surgery types, only 55% of women felt they had a choice of surgical treatment. Women who felt they had a choice were more likely to be younger(55 vs. 61; p=0.0009), more knowledgeable about equivalent survival outcomes(24% vs. 12%, p+0.0170), and shared decision making(Cronbach α=0.79) with their physician(92% vs. 88%, p=0.0066). When taking into account the patient's stage of cancer, there was no difference in the feeling of choice based on race/ethnicity, income level, or education level. This feeling of having a choice in the surgical procedure performed was not related to type of surgery: 57% of women with mastectomy felt they had a choice, while 56% of breast conservation surgery patients felt they had a choice.  Conclusions: There is a difference between mentioning treatment options during preoperative evaluations and counseling of women with newly diagnosed early-stage breast cancer, and shared decision-making. Shared-decision making is associated with a greater sense of choice, which can affect health status and may influence patients satisfaction with overall treatment. Surgeons should involve women in discussion of treatment options, regardless of education or race, as this can influence patient's sense of choice, which in turn, can affect health status.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5098.
Lapatax: a phase I study of neoadjuvant lapatinib combined with docetaxel in Her2/neu overexpressing breast cancer (BC). EORTC protocol 10054.
Authors: Bonnefoi H , Zaman K , Nobahar M , Koch KM , Pierga J , Campone M , Brain E , Bartlett J , Marreaud S , Bogaerts J , Cameron D
Published: December 2010

Abstract #5112

Background: Lapatinib (L) has been shown to be an effective anti-HER2 therapy in advanced breast cancer, and is under study as an adjuvant therapy in the ALTTO and TEACH studies. Whilst there are ongoing neoadjuvant studies with the combination of Lapatinib and paclitaxel, there are none with docetaxel (D), considered by many to be the most active taxane in breast cancer, mainly due to the limited data available on the safety and efficacy of this combination. Hence there is a need for this dose-finding study which is being conducted as a prelude to a randomized phase II trial.  Objective: The objectives are to establish the maximum tolerated dose (MTD), to characterize Dose limiting toxicity (DLT) and to define the recommended dose for phase II.  Patients and Methods: Female patients (pts) with locally advanced, inflammatory or large operable BC are treated with escalating doses of L from 1000 to 1250 mg/d, administered orally once daily continuously in combination with D given every 21 days at dose ranges of 75 to 100 mg/m² for 4 cycles. At least three pts are treated at each dose level (DL). DLT is defined during cycle 1: any grade 3-4 non hematological toxicity, ANC<0.5 G/L lasting for 7days or more, Febrile neutopenia or thrombocytopenia <25 G/L. Growth factors are given only in case of clinical symptoms. Core biopsies are mandatory at baseline and after cycle 4. Pharmacokinetic samples are collected on day 1 of cycles 1 and 2.  Results: As of June 10, 10 pts with a median age of 56 years (range 17-64) were enrolled and 3 DLs (DL 3: L 1000 mg/day, D: 85 mg/m²) have been fully investigated. No pt had a DLT during cycle 1. The toxicity profile for 30 documented cycles is summarized in this table.    The 4th cycles LVEF has been documented in 4 patients, one of whom had a drop by 16% to a value of 55%.  Conclusions: The toxicity of docetaxel-lapatinib during the first 3 dose levels is excellent. Final toxicity data and PK results of this phase 1 will be presented at the meeting.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5112.
Bevacizumab combined with chemotherapy significantly improves pathologic complete response in patients with operable or locally advanced breast cancer.
Authors: Makhoul I , Vicki KS , Korourian S , Henry-Tillman RS , Siegel ER , Westbrook KC , Hutchins LF
Published: December 2010

Abstract #5114

Bevacizumab (B) improved progression free survival in metastatic breast cancer (BC) when added to chemotherapy (CT) and was relatively safe in the adjuvant setting. This study evaluated pathologic complete response (pCR) and safety of B with CT in the neoadjuvant setting.  Methods: This is a single arm, single institution phase II trial. Patients (Pts) eligible for the study were women with proven BC (T1-4 and/or positive axillary LN -excluding inflammatory BC). Pts received CT with docetaxel (T, 75 mg/m2), cyclophosphamide (C, 500 mg/m2) and B (15 mg/kg), TCB every 3 wks x 4 cycles followed by doxorubicin (A, 60 mg/m2) every 3 wks for 4 cycles. After CT, Pts were evaluated clinically (clinical complete or partial response cCR or cPR), by mammogram and for their heart function by MUGA. Breast conserving surgery was considered if the response was deemed satisfactory, otherwise mastectomy was performed and pCR was evaluated. 28 to 84 days after surgery and after documented healing of the operative incision, B was restarted at 15 mg/kg x 9 cycles. XRT, herceptin and endocrine therapy were given as indicated concurrently with B.  Results: As planned, 40 Pts were enrolled. Average age 46 (range 27-73). One patient withdrew consent after 2 cycles of TCB. Average tumor size was 5.26 cm (range 1.8 - 15 cm). Lobular 7/ductal 32. Grade I/II/III: 3/12/24. ER +/PR +: 11; ER+/PR-8; ER-/ PR +: 3, ER-/PR-:17. HER2 +: 8. Triple negative: 14. Lymph nodes were + in 25 patients. 32 Pts completed all pre-op CT cycles. One Pt died after 2 cycles of TCB of bilateral PE, 4 Pts received a truncated doxorubicin course due to side effects, 2 Pt received TCB x 2 followed by A x 4. The most common grade 3/4 AEs (#): diarrhea (4), febrile neutropenia (4), musculoskeletal pain (10), fatigue (8), mucositis (3), nausea (2), hypertension (5), syncope (2) infection (3). No clinically significant change in LVEF was noticed (Pre-CT EF 63.3% (55-76%); post-CT EF 61.2% (49-72%)). 4 Pts had a decrease of EF > 10. 21 cCR and 16 cPR were seen.1 Pt had progression and 1 Pt had no change. 38 Pts underwent surgery. 10 had lumpectomy (average pre-CT size 4.8 cm) and 28 had mastectomy (average pre-CT size 6.1 cm). One Pt had infusaport infection and another had breast implant infection, both required device removal and had delayed wound healing. 16 pCR/39 in the breast and 13 pCR/39 in the breast and axilla were seen (pCR breast 41%, pCR breast and axilla 33%). Several Pts had near pCR. Post-operative B safety data will be presented.  Conclusions: When added to CT, B improved pCR in a poor prognostic BC Pts and was associated with manageable toxicity.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5114.
Multicenter phase II study of neoadjuvant capecitabine (X), docetaxel (T) ± trastuzumab (H) for patients (pts) with locally advanced breast cancer (LABC): final analysis.
Authors: Wildiers H , Neven P , Christiaens M , Fesneaux G , Amant F , Weltens C , Smeets A , van Limbergen E , Debrock G , Renard V , Paridaens R
Published: December 2010

Abstract #5115

Background: Addition of X to T significantly improves RR, TTP and OS vs T alone in metastatic breast cancer (MBC). Addition of X to first-line TH in HER2-positive MBC significantly improves PFS and TTP. X and T are synergistic with H in HER2-positive tumors. We present final efficacy data of TX ±H in LABC.  Materials and methods: Pts with newly diagnosed invasive stage III inoperable BC (cT4 and/or cN2–3) received X (900 mg/m2 orally bid d1–14) + T (36 mg/m2 i.v. d1&8) q3w x6, followed by surgery and radiotherapy. Pts with HER2-positive tumors (IHC 3+ or FISH+) also received H (8 mg/kg d1 of the first cycle and 6 mg/kg d1 of subsequent cycles). Safety was evaluated after each cycle, clinical response after 3 and 6 cycles, and pathological complete response (pCR) postoperatively (pCR = no residual invasive tumor in breast and axilla).  Results: Between Dec 2003 and Dec 2007, 43 pts with HER2-positive LABC were treated with TXH and 52 with HER2-negative LABC received TX. pCR rate was 21/43 (49%) with TXH and 10/52 (19%) with TX. In the TXH cohort, pts without pCR included 1 pt with disease progression and 2 pts who refused mastectomy after chemotherapy. At the meeting, full data on the whole group, including baseline characteristics and toxicity, will be presented.  Conclusions: TX±H, a neoadjuvant regimen without anthracyclines, is an effective regimen in the neoadjuvant setting. pCR rate is lower in the TX arm (19%) than in the TXH arm (49%). This shows the important contribution of H in achieving pCR, although the different biology of HER2-positive tumors might also account for differences in efficacy. TX is an attractive regimen to combine with H since it is a highly effective regimen and less cardiotoxic in contrast with anthracycline based regimens.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5115.
Triple negative breast cancer confers higher recurrence rates after breast conserving therapy.
Authors: Zaky SS , Lund M , May KA , Godette K , Holmes L , O'Regan R , Butler EN , Hair BY , Phillips R , Styblo T , Landry J
Published: December 2010

Abstract #5127

Purpose  There has been a recent surge of information regarding the treatment outcomes for women with estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative breast cancer; known as the triple negative (TN) subtype. The purpose of this study is to evaluate the impact of these receptor expressions on local, regional and distant recurrences, and overall survival (OS) in patients undergoing breast conserving therapy (BCT).  Patients and Methods  The study population included 475 primary invasive female breast cancer patients (excluding Stage IV); who were residents of Fulton-Dekalb counties in Atlanta when diagnosed in 2003-2004 and treated within the Emory University affiliated hospitals. Data was obtained from the SEER cancer registry and augmented with medical record abstraction. Median follow-up was 3.4 years. The endpoints of the study were local, regional and distant recurrences, and OS. Tumors were subgrouped as: ER-/PR-/HER2- (TN), ER+/PR+/HER2-, ER+/PR+/HER2+, ER+/PR+/HER2-. Chi-square and Fisher exact tests were employed.  Results  For the entire population, median age was 58 years. TN tumors accounted for 17% of the cases. Of the TN patients, 78% were African-American (p<0.01) and 40% had BCT. The majority of TN tumors were high grade (71%), p< 0.01. Total recurrence was 33% among the TN patients vs. 14% in the combined non-TN patient group, p< 0.01. Death occurred among 29% of TN vs. 14% of non-TN, p< 0.01.  For the patients that were treated with BCT, 94% of TN patients completed their adjuvant radiation therapy and 73% received chemotherapy. Of those receiving BCT, recurrence was 28% for TN patients and 6% for non-TN patients (p<0.01). Local recurrence was 9% and 4% for TN and non-TN patients, respectively and distant metastatic rate was 16% versus 2% respectively (p< 0.01). There were no regional recurrences in the BCT group. Time to recurrence, OS, time to death, and breast cancer specific death did not differ between the two groups.  Conclusion  A significant increase in local recurrence and distant metastatic rates were observed after BCT among patients diagnosed with TN breast cancers; however there was not a significant short-term survival difference between the TN and non-TN receptor groups. The complexity of this patient population within the conventional treatment algorithm warrants further investigation to reduce local and distant recurrences.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5127.
Prone versus supine breast irradiation in early stage breast cancer patients.
Authors: Trela K , Eberhardt B , Bereza I , Misztal L , Gabrys D
Published: December 2010

Abstract #5130

Introduction  External beam radiotherapy for breast cancer patients is necessary after breast conserving therapy. Volume of breast tissue which needs to be irradiated is close to critical structures such as lung, heart; therefore an alternative prone position could be used to improve dose homogeneity during radiotherapy. The purpose of this study was to compare dose distribution within target and normal tissue volumes between two radiotherapy plans in prone and supine position in women with large and also with small breasts.  Material and methods  36 early breast cancer patients (15 – right side and 21 left side, 7 – small, 9 - median, and 20 – large breast size) in clinical stage T1-2N0 were treated with breast conserving therapy and were dedicated for further radiotherapy. Planning CT was performed in a prone and supine position and two treatment plans for each patient were developed using conventional tangents technique. Dose volume histograms were produced and plans were compared with regard to dose volumes parameters. Comparison of the different techniques was statistically analyzed using the Wilcoxon signed rank test.  Results  The mean doses to the target volume were (50.9 Gy ± 0.59 for supine position and 50.3 Gy ± 0.81 for prone position, p=0.005), minimum dose (39.9 Gy ± 3.7 vs. 38.7 Gy ± 7.7, p=0.6) and maximum dose (54.9 Gy ± 0.5 vs. 54.4 Gy ± 0.9, p=0.02), the dose in 95 % of PTV was significantly higher in supine compare to prone position (48.0 Gy ± 1.3 vs. 46.7 Gy ± 1.8, p=0.0002). The percentage of ipsilateral lung receiving specified dose were significantly higher in supine position compare to prone position: V5 Gy was 26.8% ± 9.5 for supine position and 7.7% ± 6.4 for prone position (p<0.0001), V10 Gy was 18% ± 7.9 vs. 4.8% ± 4.6 (p<0.0001) and V20 Gy was 12.1 ± 4.9 vs. 2.7% ± 2.8 (p=0.0001). Furthermore, the maximum and mean dose to the ipsilateral lung and heart was lower in prone position (max/mean lung 44.4/2.2 Gy, max/mean heart 27.9/2.4 Gy) compare to supine position (max/mean lung 51.4/7.8 Gy, max/mean heart 30.8/3.4 Gy).  In the last part we precisely evaluated dose to the heart in left side breast patients. In this case there was significant decrease in maximum, mean and dose to the heart in prone position (max/mean heart 42.9/3.3 Gy, for prone position and max/mean heart 48.1/5 Gy for supine position). There was also smaller heart volume which received 5 Gy (10% ± 5.7 vs. 15.5 ± 11.1). Decrease in dose to the organ at risk was seen not only in large breast size patients but also in patients with smaller breasts.  Conclusion  Irradiation of patients in prone positions compare to supine positions did not improved dose distribution within target volume. Using plans generated in prone position we were able to reduce the dose to the organ at risk especially ipsilateral lung and heart.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5130.
Radiotherapeutic management of isolated local-regional recurrence following mastectomy.
Authors: Chen J , Guo X , Pan Z , Feng Y , Jiang G
Published: December 2010

Abstract #5135

Background: Postmastectomy isolated local-regional recurrence(ILRR) remains a therapeutic challenge. This retrospective study aims to evaluate the role of radiotherapy(RT) in these patients and to analyze factors that influence local-regional control and survival.  Methods: 255 pts with chest-wall(CW) and/or regional nodes recurrence(supraclavicular SC, axillary AXI and internal mammary nodes IMN) as first failure and received RT during 1990 and 2005 were analyzed, included 109 CW recurrence only, 114 regional nodes only and 32 pts with both, resulted in 304 recurrent sites. The median dose was 60Gy(47-74). Systemic treatment was give to 190 pts, including chemotherapy in 171, endocrine therapy(ET) in 69, and both in 41 pts.  Results: The median disease-free interval(DFI) was 22 mo(2-260 mo), which were 37 and 17 mo in pts with positive hormonal receptor (HR) and negative HR respectively. Median follow-up was 45 mo (9 mo -15.5 yrs). The 2, 5 and 8-yr overall survival rate was 86.4%, 56.5% and 35% respectively. Median survival time after recurrence was 79 mo. The 2, 5 and 8-yr local control rate was 56.1%, 36.3% and 27.6% respectively. 79 second recurrence in the initial recurrent region and 83 subsequent recurrence in other local-regional sites were found.    CW is the most common site of second recurrence. Multivariate analysis showed that no CW involvement, non-diffuse recurrence and radiation to the entire recurrent region were independent prognostic factors on local control of initial recurrent sites. ET proved to be the only independent prognostic factors on subsequent recurrence in other sites. In pts with CW recurrence, small field(67 pts) resulted in significantly lower 5-yrs local control compared to entire CW irradiation(74 pts) (33.6% vs 55.6%, p=0.023). Cox regression model found that DFI≥1yr, positive HR, solitary CW or non-supraclavicular nodal recurrence were independent favorable prognostic factors on overall survival .  Conclusions: RT is an effective approach for ILRR after mastectomy. Radiation fields should cover the entire recurrent region. Elective irradiation to the CW in pts with nodal recurrence is recommended. Prognostic Index based on the positive multivariate analysis could be established as to stratify different prognostic sub-groups.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5135.
Local recurrence rates in the conserved breast after MRI targeted radiotherapy.
Authors: Beresford MJ , Whipp E , Sawyer E , Halliwell M
Published: December 2010

Abstract #5143

Background: To optimise the effects of whole breast irradiation after breast conservation surgery, precise identification and delineation of clinical target volumes is essential. If the site of the “post-operative cavity” (POCx) is inaccurately located, any target miss of residual cancer cells may lead to underdosing and thus impact on local recurrence rates and survival. Studies with surgical clips have shown rates of geographical miss of the POCx to be worryingly high for radiotherapy boost doses (up to 87%). Of even more concern is that the whole breast tangential fields frequently miss the tumour bed even though the fields appear adequate based on external landmarks (in approximately a quarter of cases). MRI has subtle breast tissue characterisation that may demonstrate post-operative detail more clearly than CT and more accurately than surgical clips.  Methods and Materials: Simple opposed tangential fields were defined by surface anatomy in the conventional manner in 221 consecutive patients. Following MR imaging, fields were modified by a single radiation oncologist (EW) to encompass the POCx with a 10mm margin. Patients were treated to a dose of 45Gy in 20 fractions or 50Gy in 25 fractions, with or without an electron boost to the tumour bed (usually 12.5Gy in 5 fractions). Genetic analysis, using genome wide single nucleotide polymorphism (SNP) arrays and loss of heterozygosity (LOH), was performed on all local relapses to distinguish true recurrences (TRs) from new primaries (NPs)  Results: This cohort was at relatively high risk, with only 9.8% classified as low risk by St Gallen criteria. 43.4% were grade 3 and 19.9% had surgical margins <1mm. 62.4% of patients received boosts to the tumour bed. After a median follow-up of 5 years there were 3 local recurrences. This is an actuarial 5-year local relapse rate of 1.3%. Genetic analysis showed that 2 local relapses had identical genetic profiles to the initial primaries; they were TRs. The other was genetically distinct; it was an NP.  Conclusions: In this cohort of relatively high risk patients, the TR rate was 0.9% at 5 years. These figures compare favourably with the EORTC boost trial and the START results, although both of these studies had different inclusion criteria, particularly with regard to surgical margins. Theoretically, TRs should be the type of relapse most likely to be avoided by accurate coverage of the post-operative complex. Radiotherapy planned with guidance from MR images may cover the clinical target volume more accurately than treatment guided by anatomical landmarks alone.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5143.
Utilization of tomotherapy-based topotherapy for emerging breast radiation techniques: boost integration and accelerated partial breast irradiation.
Authors: McIntosh A , Sheng K , Khandelwal SR , Arthur DW , Ruchala KJ , Olivera GH , Jeswani S , Read PW
Published: December 2010

Abstract #5148

Background: Helical Tomotherapy-based intensity modulated radiation therapy (IMRT) can be delivered using fixed gantry angles, known as Topotherapy, with daily image guidance. With the advent of accelerated or hypofractionated treatment schemes to shorten courses of radiation, conformality and accuracy is imperative for breast radiotherapy techniques since high doses of targeted radiation are used. The purpose of this study was to characterize the dosimetry of Topotherapy for delivery of Accelerated Partial Breast Irradiation (APBI) and hypofractionated Simultaneous Integrated Boost (SIB) breast irradiation in comparison with conventional techniques.  Materials and Methods: Ten patients with early stage left sided breast cancer were evaluated for this study using Topotherapy planning. The planning target volume (PTV) was contoured as the lumpectomy cavity with a 1.5cm margin, and the breast was defined by the tissue encompassed by tangent fields minus the PTV and 5mm of skin. To evaluate SIB, nine patients were comparatively planned using a standard sequential treatment of 50Gy tangents to the whole breast with a 10Gy electron boost in 30 fractions versus Topotherapy integrated boost with the same cumulative dose in 25 fractions versus hypofractionated Topotherapy with 42.4Gy to the breast and 51.2Gy to the PTV in 16 fractions. For evaluation of APBI, 3cm hypothetical lumpectomy cavities were contoured in the four breast quadrants of a single patient, with a similar 1.5cm expansion and breast volume. Plans to deliver 38.5Gy in 10 fractions were generated for each lesion using Topotherapy and compared to 3-dimensional conformal radiation therapy (3DCRT) and IMRT using the dosimetric guidelines from the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol.  Results: Target coverage and dose to heart and lung were clinically equivalent when comparing Topotherapy APBI and SIB to conventional techniques. For ABPI, the Topotherapy conformality index was superior to 3DCRT for all breast quadrants, but inferior to IMRT for lesions located in the medial quadrants of the breast. For SIB, Topotherapy provided an improvement in conformality over conventional sequential techniques, however there was no intensity modulated comparison. Equivalent target uniformity was observed in all APBI techniques however for SIB, Topotherapy provided a superior uniformity index for the whole breast target.  Discussion: Topotherapy is capable of delivering clinically acceptable dosimetry for accelerated or hypofractionated breast radiation without compromising dose to structures at risk. This treatment modality will be utilized in the near future pending FDA approval.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5148.
Radiofrequency ablation treatment for small breast cancer.
Authors: Noguchi M , Earashi M , Motoyoshi A
Published: December 2010

Abstract #5155

Aims: There is increasing demand for minimally invasive and non-surgical treatment in breast cancer. Although radiofrequency (RF) ablation seems the most promising non-surgical treatment for small breast cancer, its relevance has been controversial. This study was performed to determine the feasibility and the safety of treating small breast cancer with RF ablation. Methods: In this study, all patients had a localized breast cancer of 2.0 cm or less in greatest diameter. The tumors were confirmed to be localized lesions by ultrasonography, mammography, and enhanced MRI or CT. Before treatment, core needle or mammotome biopsy was performed to obtain the tumor tissue for establishing the histological diagnosis and the status of hormonal receptors and HER-2 expression. A model 15000 generator with a seven-array Starbusrt XL needle-electrode Model 70 (RITA Medical System) was used for RF ablation. In the first series, 17 patients underwent RF ablation and sentinel lymph node (SLN) biopsy followed immediately by wide resection (n=13) or total mastectomy (n=4). Axillary dissection was performed in 5 patients with positive SLN. On the other hand, 15 patients underwent RF ablation and SLN biopsy in the second series. Axillary dissection was performed in 3 patients with positive SLN. The ablated lesion was excised by mammotome after several months later. The ablated tumor tissue was examined histologically with H&E staining and NADH-diaphorase staining to assess tumor cell viability. Patients who underwent wide resection or RF ablation alone received breast irradiation, and all of the patients were treated with systemic therapy according to the St. Gallen recommendation. Results: Histological examination with H&E staining revealed a spectrum of changes ranging from complete coagulation necrosis to normal-appearing tumor cells, but NADH-diaphorase staining revealed no viable tumor cells in the either series. No patient developed to local or breast recurrence in the first series with a median follow-up period of 46 months (range: 34-61 months), and in the second series with a median follow-up period of 23 months (range: 12-32 months). However, one patient in the first series and another in the second series developed to the distant metastases, although they are alive with systemic treatment. The cosmesis of conserved breast was excellent in the second series more than in the first series, and no adverse effect such as skin burn or persistent hard lump was observed in the second series. Conclusions: RF ablation is feasible for small breast cancer. To achieve wide acceptance, however, further studies are needed to determine whether the use of RF ablation for small breast cancer can provide local control and survival rates equivalent to those of conventional breast-conserving treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5155.
Evaluation of microtubule associated protein tau expression as prognostic and predictive marker in the NSABP-B 28 randomized clinical trial.
Authors: Pusztai L , Jeong J , Gong Y , Ross JS , Kim C , Hortobagyi GN , Paik S , Symmans WF
Published: December 2010

Abstract #54

Objective: We assessed Tau protein expression in patients who participated in the National Surgical Breast and Bowel Project (NSABP)-B28 clinical trial using immunohistochemistry. Expression levels were correlated with disease-free (DFS) and overall survival (OS) and we also examined if there is interaction between this marker and paclitaxel efficacy. Patients and Methods: Tissue microarrays were available for 1942 patients (63 % of all trial participants) who were included in the NSABP-B28 clinical trial and were randomized to receive either 4 courses of doxorubicin/cyclophosphamide (AC) or AC followed by 4 additional courses of paclitaxel (ACT) adjuvant chemotherapy. All patients with hormone receptor positive tumors also received adjuvant endocrine treatment. Immunohistochemistry for Tau was performed at MD Anderson Cancer Center blinded to clinical outcome. Correlation with survival was performed by the NSABP Statistical Center. Results: Forty-three percent of tumors were Tau-positive defined as equal or greateer staining than in normal breast epithelium. Tau expression correlated strongly with estrogen receptor (ER)-positive status (p<0.0001). In univariate analyses, Tau, ER and HER-2 expression as well as grade, tumor size and nodal status were each independently and significantly associated with DFS and OS (p<0.003). In multivariate analysis, the same variables except HER2 remained significant. However, there was no significant interaction between Tau expression and benefit from paclitaxel in the entire population or among the ER-positive or ER-negative subsets, respectively. Conclusion: High Tau protein expression is associated with better prognosis including longer disease-free and overall survival in patients treated with adjuvant anthracyline and paclitaxel chemotherapy and endocrine therapy. However, we could not detect a statistically significant interaction between Tau expression and paclitaxel benefit.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 54.
Surface functionalized nanoparticles for proximity-activated detection and imaging of breast cancer.
Authors: Sewell SL , Giorgio TD
Published: December 2010

Abstract #6002

Site directed therapy of metastatic and primary breast cancer promises to minimize systemic toxicity associated with chemotherapy agents that have no specificity for pathologic tissues. We have developed a multifunctionalized nanoparticle specifically designed to target breast cancer, including metastases.  Quantum dots (QDs) were functionalized with a matrilysin (MMP-7) cleavable, proximity activated substrate, PEG-peptide-PEG (PA construct), where cleavage occurs at the peptide bridge. The QDs were further functionalized with folic acid, a strong breast cancer cell targeting ligand with well-known binding to some normal tissues. The construct initially conceals the folate ligand and reduces binding to non-target tissues. MMP-7 activated cleavage of the PA construct and subsequent unmasking of the folate ligand occurs only at the site of the breast tumor, resulting in a proximity activated targeting (PAT) system. The activity of QDs functionalized with both the PA construct and folic acid (FA-QD-PA) was compared to QDs functionalized with only folic acid (QD-FA).  Cellular association of QD-FA nanoparticles with the human breast cancer cell line MDA-MB-231 revealed that 61.9 ± 6.5% of the cells were fluorescently labeled. Addition of the PA construct reduced QD-FA recognition by MDA-MB-231 cells to 2.1 ± 0.4%. MMP-7 cleavage of the protected FA-QD-PA construct restored MDA-MB-231 recognition to 21.9 ± 5.4 %, a significant increase compare to the uncleaved multifunctional nanoparticle construct (one-way ANOVA, p*<0.001, n=3). This in vitro data suggests that the PAT nanoparticle model could function effectively in vivo for specific targeting of breast cancer and metastasis. In the next phase of research, the ability of the FA-QD-PA and FA-QD nanoparticles to detect breast cancer in vivo will be tested using murine models of human breast cancer.  This work was funded by the US Army Medical Research and Material Command CDMRP under award BC043908.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6002.