bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-10-12: Wire Guided Breast Procedures with Intraoperative Ultrasound
Authors: Komenaka IK , Bouton ME , Wilhelmson KL.
Published: April 2011

Background: Wire guided breast procedures (WGBP) are the most commonly used breast conserving operation for non-palpable cancers. Suboptimal needle placement can result in a larger amount of tissue removed and increased difficulty in removal of the lesion. The use of intraoperative ultrasound can improve the execution of wire guided breast procedures by more precisely demonstrating the direction and depth of the wire as well as the location of the wire hook and radiographic clip. These benefits allow a more appropriately located incision and smaller volume of tissue removed.

Methods: A retrospective review of all patients who underwent the WGBP at a county hospital with associated surgical residency program. 28 patients underwent the procedure with intraoperative ultrasound from June 2009 to March 2010.

Results: Breast cancer patients who underwent a wire-guided lumpectomy with intraoperative ultrasound had a lower rate of positive margins (9% vs. 26%, p = 0.28) and a smaller volume of tissue removed (126 cm3 vs. 146 cm3, p = 0.57) compared to patients who underwent wire guided lumpectomy alone. In patients who underwent wire guided excisional biopsy for diagnostic purposes, the volume of tissue removed was smaller in the intraoperative ultrasound group (30 cm3 vs. 44 cm3, p = 0.17) and the targeted area was more likely to be removed in one specimen (1.1 vs. 1.5, p = 0.03) compared to those who underwent the procedure without intraoperative ultrasound. Two illustrative cases with figures are presented. The first demonstrates the benefit when the distance from skin entry point of the wire to the target area is great. The hook can be localized with ultrasound for optimal placement of the incision.

The second demonstrates potential benefit when wire placement is suboptimal and the wire hook is distant from the target. The surgeon may use the wire location to identify the approximate area of the lesion and then the exact location of the radiographic clip can be localized with intraoperative ultrasound.

Conclusions: Intraoperative ultrasound can improve surgical outcomes of the wire guided breast procedure.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-12.
Abstract P4-10-13: Therapeutic Delays, Mode of Diagnosis and Surgical Treatment of Operable Invasive Breast Cancer (BC) in Elderly Versus Non Elderly Patients in the Community
Authors: Tazi Y , Garbay J-R , Berrada N , Chevalier J , Mazouni C , Mathieu M-C , Bourgier C , Domont J , Spielmann M , Dionysopoulos D , Delaloge S.
Published: April 2011

Background: National mammography screening program covers populations aged 50-74. We wondered whether breast cancer characteristics and treatment delays were influenced by age and screening method in a community-based breast unit.

Patients and Methods: We analyzed complete data of prospectively recorded community operable breast cancer cases in a single regional cancer center between Jan 1st, 2005 and Oct 10th, 2007. Pts were eligible if they i. had a final diagnosis of invasive BC ii. were operated as first trt for BC, iii. had no history of other previous malignancy within the past 5 year period. Logistic regression analyses (SAS) were used to determine factors influencing delays between first description of the lesion and first appointment at breast unit.

Results: 1044 pts met the inclusion criteria and had full data available. Age did not appear as a predictor of therapeutic delay, with both elderly and non-elderly pts having a median delay of 19 days between first screening/evidence of disease and 1st appointment at the breast unit. 59% of elderly and 65% of non-elderly pts had respectively had their breast cancer diagnosed through mammographic screening. As expected, mammographic screening as mode of discovery of the cancer was highest, among the 688 pts aged 50-74 (73%). Tumors characteristics and surgical treatment did not differ according to age categories elderly/non elderly as described in Table 1. Conservation rates were high in both populations.

Conclusion: Despite absence of national mammographic screening program in elderly populations, patterns of screening and care appear efficient in a community-based setting, with absence of therapeutic delays, similar tumor staging and similar accesss to conservative surgery as compared to younger populations.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-13.
Abstract P4-10-14: Risk of Ipsilateral Breast Events in Patients with Ductal Carcinoma In Situ after Local Excision
Authors: Yi M , Kuerer HM , Lucci A , Meric-Bernstam F , Babiera GV , Thomas CL , Ross MI , Hunt KK.
Published: April 2011

Purpose

To determine the risk of ipsilateral breast events (IBE) in patients with ductal carcinoma in situ (DCIS) treated with local excision. Patients and Methods

We retrospectively identified 692 patients who had undergone local excision from 1968 through 2007 at our institution with a final diagnosis of DCIS. Factors evaluated included age, race, method of detection, menopausal status, bloody nipple discharge, histological type, final margin status, grade, status at last follow-up and recurrence information. An IBE was defined as the development of breast cancer of invasive histology or DCIS (but not lobular carcinoma in situ) in the treated breast.

Results

At a median follow-up of 6.1 years, 47 (6.8%) IBEs occurred in the 692 patients. Among 47 IBE, 23 (48.9%) were DCIS and 19 (40%) were invasive cancer and 5 (10.6%) were unknown type of IBE. Patients with IBE were younger (53 Vs 57, P=0.04). Whether patients had final positive margin (4 patients) had no influence on IBE. Use of a Cox proportional hazards model showed that patients with high grade tumors and those who did not receive adjuvant radiation therapy (XRT) were more likely to have an IBE (Hazard ratio: 4.1, 95% CI:1.3-13.4, P=0.019). The 5-year rate of ipsilateral breast events for patients with grade III DCIS who did not undergo adjuvant radiation therapy was significantly higher than all others: 15% vs. 4.6% compared to grade I/II with XRT, 15% vs. 10% compared to grade I/II without XRT, and 15% vs. 9.9% in grade III with XRT (P=0.017). Conclusions

Patients with low or intermediate grade DCIS have an acceptably low rate of ipsilateral breast events after local excision with adjuvant radiation therapy. Patients with high-grade lesions treated without irradiation have a rate of IBE of 15% at 6 years, suggesting that excision alone is inadequate treatment in this group. Further follow-up is necessary to document long-term results.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-14.
Abstract P4-11-03: The Impact of Fractionation on Local Relapse for Patients with Grade 3 Breast Cancer
Authors: Tyldesley S , Woods R , Speers C , Nichol A , Weir L , Olivotto I.
Published: April 2011

Background: Several randomized trials have demonstrated that hypofractionated (HF) and conventionally fractionated (CF) radiotherapy (RT) provide equivalent local control following breast conserving surgery (BCS). However, an update of the Canadian trial suggested that patients with grade 3 disease had an increased risk of local relapse after HF. The risk of local relapse following HF or CF according to grade was investigated among a population-based cohort from British Columbia, Canada. Materials and methods: Female patients diagnosed between 1990 and 2000 with T1-T2N0M0 breast cancer treated with lumpectomy, axillary dissection and RT with at least 6 nodes removed and RT delivered to the breast were identified. Whole breast RT prescriptions were distributed in two groups : HF (typically 42.5 to 44 Gy in 16 fractions), and CF (45Gy to 50 Gy in 25 fractions). The 45 Gy prescription was followed by a boost to the biopsy cavity regardless of the margin status. Patients with close or positive margins received a boost (typically 7.5 to 10Gy in 3 to 4 fractions, or 10 to 20Gy in 5 to 10 fractions). Baseline demographic (age, year of diagnosis), tumour (grade, histology, size, lymphatic vascular space invasion (LVI), presence of extensive DCIS) and treatment factors (margin status, hormonal or chemotherapy use, RT fractionation group, and RT boost use) were abstracted. Cumulative rates of local relapse were estimated using a competing risk approach (distant relapses or death were competing risks) and compared across groups using Gray's test. Factors significant on univariate analysis were included with fractionation group in a multivariate (Fine and Gray) model among grade 3 patients. Results: The cohort consisted of 1,335 patients diagnosed with grade 3 breast cancers: 252 received CF and 1083 patients received HF. The fractionation groups were well balanced for most of the aforementioned factors except median age (56 years for CF vs 52 years for HF (P<0.01), and use of systemic therapy (hormones alone: 26% vs 19%; chemotherapy alone: 27%vs 33%; and chemo+hormone therapy: 8% vs 10% (p=0.04) for HF compared to CF). The 10-year cumulative incidence rate of local relapse in patients with grade 3 breast cancers was 6.9% for the HF group and 6.2 % for the CF group (p=0.99). A Fine and Gray multivariate competing risk model showed that age under 40 years (p=0.02), positive margins (p=0.05) and negative ER status (p=0.01) were associated with an increased risk of local relapse, but fractionation group was not (Hazard ratio=0.95, p=0.88).

Conclusions: There was no evidence that hypofractionation was inferior to conventional fractionation for breast conserving therapy in patients with T1-T2 N0, grade 3 breast cancer in a population-based series.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-03.
Abstract P4-11-07: Quantitative Coronary Angiography Findings of Patients Who Received Previous Breast Radiotherapy
Authors: Wang W , Wainstein R , Freixa X , Dzavik V , Fyles A.
Published: April 2011

Purpose: To compare the coronary angiographic findings, between patients who had previous left sided breast radiotherapy (RT) and those who had right sided RT.

Methods: Between 1995 and 2009, 12696 patients who underwent curative RT for breast cancer in Princess Margaret Hospital were screened to check if they had a post-RT coronary angiogram. Two cardiologists, blinded to treatment, assessed all angiograms and measured the percentage of stenotic lesions and the mean diameter of each segment of the left anterior descending artery (LAD) and the right coronary artery (RCA) using Quantitative Coronary Angiography (QCA).

Results: Ninety-one patients were included, 49 and 42 patients had left sided RT and right sided RT respectively. The median time from RT to coronary angiogram was 4.4 years (range: 22 days - 16.9 years). Nineteen patients (39%) in the left sided RT group and 17 (40%) in the right sided RT group needed coronary revascularization (percutaneous coronary intervention or by-pass surgery). The LAD territory was revascularized in 14 (29%) and 11 (26%) patients respectively. The degree of stenoses and mean vessel diameter were not significantly different between the two groups.

Table 1: Quantitative

The proportion of patients who developed clinically significant stenoses of coronary arteries were not statistically different between the two groups.

Table 2: Patiens

In 32 patient who had coronary angiograms >5 years after breast RT (16 left-sided and 16 right-sided), the only statistically significant finding (P<0.05) was marginally narrower mid RCA segments among those who had right sided RT: 2.52 mm versus 2.92 mm (P = 0.039). Conclusions: Left sided breast RT did not increase the risk of premature coronary artery disease as compared with right sided RT. However, with the limitation of short duration between radiotherapy and coronary angiogram, late development of coronary artery stenoses 10-15 years after left sided RT can not be excluded.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-07.
Abstract P4-11-16: Accelerated Partial Breast Irradiation for Ductal Carcinoma In Situ: An Analysis of the Susan G Komen Clinical Trial
Authors: Abbott AM , Gay J , Han L , Kinney M , Washington T , Tuttle TM.
Published: April 2011

Introduction

In 2002 the Food and Drug Administration approved a device, MammoSite, that delivers accelerated partial breast irradiation (APBI). Our aim was to determine outcomes with MammoSite in the treatment of ductal carcinoma in situ (DCIS). Methods

We conducted a prospective multi-center trial between 2003 and 2009. Inclusion criteria included age > 18 years, biopsy diagnosis of DCIS, and no prior breast cancer history. Patients underwent breast-conserving surgery plus MammoSite placement. Radiation was given twice daily for 5 days for a total of 34 Gy. Patients were evaluated for development of toxicities (according to the EROTC/RTOG Acute Radiation Morbidity Scoring Criteria), cosmetic outcome, and ipsilateral breast tumor recurrence (IBTR). Results

We enrolled 45 patients into the study. APBI was not initiated in 5 patients due to inadequate distance from tumor cavity to the skin. Toxicities were observed in 30 patients (75%). Grade 1 toxicity was the most common (78%); most were subcutaneous and cutaneous changes. Cosmetic outcome at 12 months was reported as good to excellent in 93% of surgeon and 90% of patient responses. Median follow up was 36.5 months. Among treated patients, 4 (10%), developed an IBTR, (all DCIS). All IBTRs were outside the treatment field. Among patients with IBTRs the mean age was 49.8 years and the mean time to recurrence was 29.8 months.

Conclusions

APBI, using MammoSite, appears to provide a safe cosmetically acceptable outcome; however the 10% IBTR rate with median follow up of only 36.5 months is concerning. Randomized trials are necessary before use of APBI for DCIS.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-16.
Abstract P4-11-17: Can We Specifiy the Minimum Breast Size at Which Therapeutic Mammoplasty Should Be Considered To Mitigate Radiotherapy Toxicity in Patients Undergoing Breast Conserving Surgery for Breast Cancer?
Authors: Lambert KV , Tanteles GA , Mills J , Murray R , Chakraborti P , Chan S , Cheung KL , Osman A , Peat I , Woodings P , Barwell J , Talbot C , Symonds P , Shokuhi S , Stotter AT.
Published: April 2011

Background

For breast cancer patients undergoing breast conserving surgery, local complications after breast radiotherapy have in the past been shown to be proportional to breast size. Therapeutic mammoplasty is an option to extend the role of breast conserving surgery. In our units, it has been used in larger breasted women undergoing breast conserving surgery to reduce the risk of local radiotherapy complications.

Aim

The aim of this multicentre study was to determine, with modern radiotherapy dosing schedules, if it is possible to specify a minimum bra cup size at which therapeutic mammoplasty should be considered.

Methods

Recurrence free breast cancer patients (at least 3 years post conservative surgery and radiotherapy) were identified from three oncology follow up clinics in the United Kingdom.

50Gy in 25 fractions over 5 weeks prescribed to the 100% isodose at the ICRU reference point, on the central outline of the breast had been a typical dosing schedule. Radiotherapy effects were graded using the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) score. A score of two or above was taken as representing that the particular toxicity variable was present. The relationship between radiotherapy toxicity variables was calculated using the Pearson correlation co-efficient.

Results

479 breast cancer patients were assessed. Increasing cup size correlated with oedema (Pearson correlation co-efficient r=0.30, p=<0.0001), induration (r=0.31, p=<0.0001), telangiectasia (r=0.24, p=<0.0001), breast retraction (r=0.15, p=0.002) and pain (r=0.10, p=0.030). 2.3% of patients with cup size AA/A exhibited fibrosis, 6.6% with cup size B or C, 11.8% cup size D and 25.5% with cup size DD and above. Conclusion

Local radiotherapy complications following breast conserving surgery for breast cancer remain proportional to breast size even with modern radiotherapy equipment and dosing schedules. This effect is most pronounced in women with a bra cup size D and above. For these women, therapeutic mammoplasty should be considered. Further work to identify the genetic determinants of normal-tissue radiation damage is underway to optimise the surgical decision.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-17.
Abstract P4-11-20: Integration of SPECT/CT Lymphoscintigraphy into Breast Cancer Radiation for Lymphatic Sparing
Authors: Cheville AL , Petersen IA , Brinkman DH , Ward SB , Mullan BP , Durski J , O'Connor MK , Schomberg PJ , Yan E , Garces YI , Laack NN.
Published: April 2011

Lymphedema (LE) is a common complication of cancer treatment, and has been identified as the number one issue by breast cancer survivors with incidence as high as 70%. Given the long-term survivorship of these women, LE is a widely prevalent condition. Irradiation of axillary and supraclavicular lymph nodes increases a patient's risk of LE onset and progression by as much as 2-fold. It is anticipated that a more individualized approach to post-surgical irradiation of breast cancer patients may reduce radiation-induced lymph node (LN) damage without sacrificing control rates, although it is noted that a definitive radiation exposure threshold below which LNs physiological integrity will be preserved is currently lacking.

To identify the locations of the small, non-pathological but physiologically relevant LNs which drain the arm after breast cancer surgery and incorporate them into radiation planning, filtered 99mTc sulfur colloid (TcSC) was administered and a SPECT-CT scan was acquired for 22 patients immobilized in the treatment position. These images were registered with the Radiation Oncology planning CT scan, and draining LN were contoured automatically using a threshold of 50% maximum intensity.

Two treatment plans were generated for each patient, one per routine clinical practice (STD) and the other (MOD) with treatment fields modified to minimize dose to the LNs visible on SPECT/CT images while ensuringthat ≥50Gy or biologic equivalent is delivered to target tissues. 53 draining LN were identified, 54% of which were inside the STD plan fields but could be blocked in the MOD plan fields. 62% of LN in the STD plans vs. 17% in the MOD plans receiving a mean of ≥10Gy, and 27% in the STD plans vs. 6% in the MOD plans receiving a mean of ≥40Gy.

Patient-specific LN dose reduction can be achieved through integration of SPECT/CT images into the radiation planning process. These patients will be followed for the development of LE, to estimate an exposure threshold below which LN preservation is assured.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-20.
Abstract P4-11-21: Dosimetric Comparison of Radiotherapy for Left Sided Breast Cancer: Breath-Hold Versus Free-Breathing
Authors: Zagar TM , Palta M , Catalano S , O'Neill L , Yoo S , Horton J , Prosnitz LR.
Published: April 2011

Background: Radiotherapy for left sided breast cancer potentially increases risk for late toxicity to the heart. The simple technique of breath-hold (BH) can be instituted in an attempt to reduce volume of lung and heart irradiated in tangential fields. We report on patients with left sided breast cancer that were planned both with conventional free-breathing (FB) and BH radiation techniques from a single institution.

Methods: From 10/2006 to 5/2010, 20 patients with node-negative, early stage breast cancer underwent CT simulation for left sided breast cancer and were selected for analysis in this report. FB and BH CT scans were obtained and treatment plans using opposed tangential fields were created to compare various dosimetric indices.

Results: BH plans resulted in lower doses to the heart (max dose 1774 vs. 4560cGy, P<0.0001; mean dose 175 vs. 296cGy, p=0.0178; V25 0 vs. 1.85%, P<0.0001; volume in tangential field 0 vs. 10.11cc p=0.0002) compared to FB. The ipsilateral lung received lower doses but a larger volume of lung was encompassed in the tangential fields (V20 13.32 vs. 20.32%, P<0.0001; mean dose 741 vs. 1025cGy, p=0.0003; volume in tangential field 198.8 vs. 256.8cc P<0.0001) compared to FB.

Conclusions: Treatment of early stage left sided breast cancer with BH technique is a simple method for minimizing cardiac and ipsilateral lung dose. Long term follow-up is necessary to demonstrate if these dosimetric differences translate into clinically meaningful differences.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-21.
Abstract P5-01-06: 18[F]-FDG Tumoral Uptake and Metabolic Response after 1 Cycle of Primary Chemotherapy According to Tumoral Phenotype of Breast Cancer
Authors: Berriolo-Riedinger A , Humbert O , Riedinger J-M , Arnoud L , Coudert B , Dygai-Cochet I , Cochet A , Toubeau M , Fumoleau P , Brunotte F.
Published: April 2011

To compare the 18[F]-FDG-PET (PET) metabolic characteristics in triple-negative, luminal and positive HER2 breast cancer. Material and Methods: One hundred and forty-five patients with newly diagnosed locally advanced breast cancer were evaluated. Twenty one metastatic patients (discovered in baseline PET) were excluded and 9 patients were lost. One hundred and fifteen had undergone FDG PET before and after the first course of neoadjuvant chemotherapy. Breast cancer lesions were imaged at 80-90 minutes after administration of FDG. Maximum standardized uptake values (SUV) were measured at both time point (SUV1 and SUV 2). Metabolic response was measured by the relative decrease of SUV (ΔSUV). Using Immunohistochemistry as a surrogate for expression profiling, the tumours were classified as follows: triple negative defined by the lack of oestrogen receptors, progesterone receptors and human epidermal growth factor receptors 2 (HER2) expression, luminal (hormonal receptor positive, HER2 negative) and HER2 positive (overexpression of HER 2). Relationships between baseline [18F]-FDG uptake and clinical, histopathological and biological parameters were assessed by Mann-Whitney test. Relationships between SUV1, SUV2, ΔSUV and the tumoral phenotype were assessed by Kruskal-Wallis test.

Results: In the overall population the mean ±SD SUV1, SUV2 and ΔSUV values were 6.7± 5.9, 3.7± 3 and −36.7% ± 35.7%, respectively. Significant relationships were found between baseline FDG uptake and initial clinical and histopathological parameters : a high mitotic activity (p≥0.0001), a high nuclear pleomorphism (≥0.0002), a high tumour grading (p≥0.0001) and a negative oestrogen hormonal receptor status (p≥0.0001) were associated with a high baseline SUV. Patient age, lymph node involvement, architectural differentiation, progesterone hormonal receptor and HER2 status were not found to be related with SUV values.

Metabolic characteristics (mean ± SD) according to tumoral phenotype:

Conclusion: Our results show a significant positive relationship between the baseline FDG uptake and the proliferation markers, the tumour grading, the number of mitoses and the nuclear pleomorphism. A significant negative relationship was found between the baseline FDG uptake and the oestrogen hormonal receptor status. The triple negative phenotype was associated with higher baseline FDG uptake and higher residual FDG uptake after one course of chemotherapy commensurate with their aggressive biology. Luminal tumours showed a lower ΔSUV reflecting their lower chemosensibility.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-06.
Abstract P5-01-10: Tumor Optic Properties Measured Using Diffuse Optic Spectroscopy Imaging Correlate with Proliferation and Glucose Metabolism in Breast Cancer Patients
Authors: Ueda S , Cerussi AE , Carpenter PM , Roblyer D , Durkin A , Hsiang D , Mehta RS , Butler JA , Tromberg BJ.
Published: April 2011

(Background) Diffuse Optic Spectroscopy Imaging (DOSI) is non-invasive imaging technology that employs near-infrared (NIR) light to quantitatively characterize the hemodynamic and metabolic properties of breast cancer tumors.

(Methods) We utilized DOSI to measure baseline tumor concentrations of oxy-hemoglobin (ctO2Hb), deoxy-hemoglobin (ctHHb), total hemoglobin (ctTHb), oxygen saturation (stO2), as well as water and lipid content of tumors from sixteen patients with primary breast cancer prior to neoadjuvant chemotherapy. Core-needle biopsy specimens were also collected from these patients and analyzed for Ki67, Glut-1, and Fatty acid synthese (FAS), biomarkers of cancer proliferation, glucose metabolism and fatty acid metabolism, respectively. These optic and biological biomarkers were statistically compared to each other and to overall therapy response. (Results) Ki67 score was positively correlated with baseline levels of ctO2Hb (µM) (r = 0.51, p = 0.04), ctTHb (µM) (r = 0.51, p = 0.05), and stO2 (%) (r = 0.57, p = 0.02), and negatively correlated with lipid content (%) (r = -0.52, p = 0.04). Tumors with positive Glut-1 status (n=8) showed significantly higher baseline levels of ctO2Hb (26.2±12.5 v.s 19.9±10.1, p = 0.04), ctTHb (41±13.3 v.s 27.5±11.7, p = 0.05), and stO2 (81.1±6.6 v.s 70.2±9.9, p = 0.02) and lower baseline levels of lipid (49±17.1 v.s 66.2±10.4, p = 0.03) compared to those with negative Glut-1 status (n = 8). There were no correlation between FAS and the optic properties. Five (31.3%) of 16 tumors achieved pathologic complete response (pCR) after completion of chemotherapy followed by surgery. Tumors with pCR showed higher stO2, higher Ki67 score and higher likelihood of Glut-1 expression than those with non-pCR (p = 0.009, 0.01, 0.03, respectively).

Only p-values with statistical significance were described.

(Conclusion) Higher tumoral expression levels of Ki67 and Glut-1 were correlated with higher oxygenation and lower lipid concentration and associated with a pathologic complete response to chemotherapy. Non-invasive optic properties measured using DOSI are potential surrogate markers for tumor proliferation and glucose metabolism.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-10.
Abstract P5-01-11: Monitoring Primary Medical Therapy with Three-Dimensional Optical Mammography
Authors: Enfield LC , Cantanhede G , Gibson AP , Hebden JC , Douek M , Purushotham A.
Published: April 2011

Background: Optical tomography is a functional imaging technique using near-infrared (NIR) light to produce three-dimensional (3D) breast images of tissue oxygen saturation and haemoglobin concentration. The advantages include the lack of ionising radiation and the quantative physiological information obtained. With increasing use of primary medical therapy, there is a need for a non-invasive functional imaging tool to evaluate response to treatment. Optical tomography was evaluated for monitoring early response to treatment.

Materials and Methods: Women with newly diagnosed breast cancer, suitable for primary medical therapy, were recruited. Changes in physiological and optical properties within the tumour were evaluated during the course of neoadjuvant chemotherapy or endocrine therapy. For patient undergoing neoadjuvant chemotherapy, optical imaging wasperformed prior to treatment, at 2 week, halfway through and on completion of chemotherapy. Images of light absorption and scatter, haemoglobin concentration ([HbT]) and oxygenation (SO2) are produced. Results: To date, ten women have been recruited to the project, and are being scanned throughout the course of their treatment. Five women are undergoing neoadjuvant chemotherapy and five are undergoing endocrine treatment prior to surgery. Nine women have been scanned more than once with five women scanned three times, and one has completed the protocol. The contrast between the tumour and the background tissue was calculated and any changes in ROI contrast and physiological parameters tracked. Initial scans show an increase in [HbT] and a decrease in SO2 in the region of the tumour. Changes in contrast and [HbT] in the tumour ROI can be seen early in treatment. A 45 year old patient was being treated with neoadjuvant taxane chemotherapy for a 26x21x34 mm Grade 2 carcinoma. The tumour [HbT] was 43.95±4.20 μM prior to treatment, falling to 25.6±6.43 μM by Week 9 and 19.19±0.36 μM by Week 18 of treatment and 23.5871± 1.6616 at the final scan. Background tissue [HbT] remained constant at ∼21±4 μM. Biopsy results classified the patient as a good responder to treatment. Initial data from other patients show changes in [HbT] at the two week scan, some showing a decrease and others show an increase in measured [HbT]. Future work will include correlation of optical data with clinical MRI findings, biopsy results and clinical outcome. Discussion: Optical imaging of the breast is feasible during primary medical therapy and can be used to assess response to treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-11.
Abstract P5-01-12: Specific Tumor Component Spectrum as a Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Xu S , Cerussi AE , Tromberg B , Gratton E.
Published: April 2011

BACKGROUND: Monitoring individual tumor response to neoadjuvant chemotherapy could provide surrogate markers for oncologists to adjust therapeutics in order to minimize collateral damage from ineffective therapies. Diffuse optical spectroscopy imaging (DOSI), by increasing the wavelength range and resolution, has been employed to characterize malignant tumor and its response to neoadjuvant chemotherapy since it measures the abundance in the four major chromophores (lipid, oxy-hemoglobin, deoxy-hemoglobin and water). Through the application of a spectral analysis method, Self-Referencing Differential Spectroscopy (SRDS) analysis, which accounts for only intersubject variability, a novel optical intrinsic biomarker which is unique to cancer was revealed. By fitting the difference spectrum between tumor and normal tissues to the four component basis spectra, the residuals disclose a spectral fingerprint called specific tumor component (STC) spectrum which contains specific absorption bands which separate normal from abnormal tissue and benign from malignant tumors.

PATIENTS AND METHODS: 14 patients were enrolled in this study and all the subjects provided informed written consent according to an institution-approved protocol. Measurements were taken pre-, post-neoajuvant chemotherapy and the midpoint in the treatment. The chemotherapy regimen is 2-4 cycles of doxorubicin-cyclophosphamide (A/C), followed by 2-4 cycles of carboplatin-taxol/abraxane-avastin (nabTC). Tumor classification was confirmed by pathology reports and 8 out of 14 patients were classified as complete responders (CR); the rest as noneresponders (NR). Pre and post-treatment STC spectra were compared in different pathological responding categories. Data were analyzed by using custom software designed for Matlab. The concentrations of NIR absorbers will be calculated from a spectral model of tissue absorption by using the basis spectra. For the SRDS method, the absorption spectra will be further analyzed by using custom software (Elantest; Laboratory for Fluorescence Dynamics, Irvine, Calif, www.lfd.edu). Details of SRDS method has been described previously.

RESULTS: The shape of STC spectra for non-responders was well preserved since insusceptible tumor structure will remain basically unaffected during the chemotherapy. Whereas in the completed responders, the therapy-induced changes in tumor microvasculature, edema, and necrosis lead to a significant dissimilarity in STC spectra.

CONCLUSION: STC spectrum, as an endogenous in vivo biomarker, can predict pathological response in breast tumors treated with neoadjuvant chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-12.
Abstract P5-02-01: FGFR Signalling Drives the Growth of Triple Negative and Basal-Like Breast Cancer Cell Lines Both In Vitro and In Vivo
Authors: Turner N , Sharpe R , Johnson D , Pearson A , Ashworth A.
Published: April 2011

Background: Substantial evidence now links aberrant signalling by the fibroblast growth factor receptors (FGFRs) to the development of multiple different cancer types. The oncogenic drivers of triple negative and basal-like breast cancers are largely unknown and we examined for a potential role of FGFR signalling in the oncogenesis of triple negative breast cancer.

Methods: We examined the sensitivity of a panel of 40 breast cancer cell lines to the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074.

Results: Triple negative (TN) breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (p=0.0028), with half (8/16) of TN cell lines demonstrating significantly reduced growth. The majority of TN cell lines demonstrated only modest sensitivity to FGFR inhibition in two-dimensional growth, but were highly sensitive in anchorage independent conditions. PD173074 inhibited down stream MAPK signalling and induced cell cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express autocrine FGF2 ligand, and RNA interference targeting of FGF2 significantly reduced anchorage independent growth. Finally, PD173074 significantly reduced the growth of basal-like breast cancer cell line xenografts.

Conclusion: Basal-like breast cancer cell lines express autocrine FGF2 and demonstrate substantial sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-02-01.
Abstract P5-02-02: Decreased Expression of Gremlin Correlates with Bone Metastasis and Poor Prognosis in Breast Cancer
Authors: Ye L , Mansel RE , Jiang WG.
Published: April 2011

Background: Bone morphogenetic proteins belong to TGF-β superfamily, which are a group of pluripotent factors, widely involved in prenatal and postnatal development and homeostasis of various tissues and organs. BMPs and their signaling have been indicated in tumorigenesis and progression of certain solid tumors. Recent studies have demonstrated a profound role played by Noggin, a BMP antagonist in bone metastasis from breast cancer, and have indicated a sound therapeutic potential. The current study examined expression of Gremlin, a BMP antagonist which is poorly understood in breast cancer, t, and its relevance to pathological and clinical parameters.

Methods: Breast cancer tissues (n=82) and normal background tissues (n=24) were collected immediately after surgery. The clinical follow-up was routinely performed after surgery. The median follow-up period was 120 months. The expression of Gremlin was examined in a breast cancer cohort using quantitative real time PCR and immunhistochemistry (IHC).

Results: IHC revealed a pattern of cytoplamic staining of Gremlin in mammary epithelial cells in breast tissues. Gremlin staining tended to be decreased in breast cancer, but there was no significant difference in its transcripts levels compared with that of normal background tissues. Gremlin transcripts were lower in both moderately differentiated and poorly differentiated tumors compared with well differentiated tumors. The level of Gremlin transcripts in primary tumors was decreased in the patients with poor prognosis (13343±6001) including those patients had local recurrence, metastases and died of breast cancer, p=0.023 when compared with 146209±56574 of patients remained disease free. This decreasing expression was also seen in the patients with disease specific bone metastases, which was 18834±13159 and p=0.032 compared to that of patients being disease free.

Conclusions: Taken together, decreasing level of Gremlin transcript in primary tumors of breast cancer correlates with bone metastasis and poor prognosis. Its implication in disease specific bone metastasis and therapeutic potential warrants further investigation.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-02-02.
Abstract P5-03-06: Progesterone Activates MAPK Pathway in Estrogen Induced Mammary Carcinogenesis
Authors: Boopalan T , Arumugam A , Delgado A , Parada J , Agullo P , Lakshmanaswamy R.
Published: April 2011

In women, breast cancer is the most prevailing endocrine-related malignancy. Epidemiological and experimental studies argue that estrogens are central to its etiology. Estrogen-induced carcinogenesis in ACI rats is highly relevant as a model for human breast cancer. These estrogen-induced cancers exhibit aneuploidy, as do invasive ductal mammary carcinomas in women. It has been demonstrated that ovary intact ACI rats given estrogen induced high incidence of mammary cancers while ovariectomized rats given the same dose of estrogen for the same length of time did not induce mammary cancers. Recently, we demonstrated that ovariectomized ACI rats given estrogen plus progesterone had a high incidence of mammary cancer. In this context, it is essential to understand the possible role of progesterone, if any, as the other main ovarian hormone in mammary carcinogenesis. Our goal was to determine the role of progesterone in mammary cancer development by using carcinogenesis induced solely by hormones in ACI rats. To achieve our goal, we designed the following experiment. Ovary intact and ovariectomized rats were used in this study. The groups (n=30) tested were as follows: 1) ovary intact control (no hormone treatment); 2) ovary intact rats given 30 mg estradiol; 3) ovary intact rats given 30 mg estradiol plus 30 mg mifepristone; 4) ovary intact rats given 30 mg progesterone; 5) ovariectomized control (no hormone treatment); 6) ovariectomized rats given 30 mg estrogen; and 7) ovariectomized rats given 30 mg estradiol plus 30 mg progesterone. Mammary glands were surgically excised and snap frozen in liquid nitrogen and stored at -80°C from a subset (n=4) of intact animals after four weeks of treatment and ovariectomized rats after twelve weeks of treatment. In rest of the animals mammary carcinogenesis was followed for nine months. As expected, estradiol induced mammary cancers in ovary intact rats and not in ovariectomized rats. Addition of progesterone to ovariectomized rats treated with estradiol induced high incidence of mammary cancer. Mifepristone treatment inhibited mammary carcinogenesis in ovary intact rats receiving estradiol. Pathway focused microarray analysis of mammary glands from the rats of different groups and treatment indicated alterations in apoptosis, MAPK and PI3K pathways. Estrogen plus progesterone treatment down regulated apoptotic genes such as Apaf1, Bad, Bax, Bid, Casp9 and up regulated Mapk3, Grb10, Itgb1, PrKca, Prkcz and Map4k1, Map2k1ip1, Mapk8ip2, Mapkapk5 in PI3K and MAPK pathways respectively when compared with estrogen alone treatment. We have observed differences both at transcriptional and translational levels. Our results clearly demonstrate the significance of progesterone in mammary carcinogenesis.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-06.
Abstract P5-04-03: Antibodies in Single Chain Format Against HER2/neu Antigen: Promising Agents for Breast Cancer Immunotherapy
Authors: Asgharpour M , Nejatollahi F , Jaberipour M.
Published: April 2011

Introduction: HER2/neu gene is overexpressed in 25-30% of breast cancers and is associated with increased metastatic potential and poor prognosis. Blocking the HER2/neu signaling has been the focus of most therapeutic approaches. Although monoclonal antibodies have shown some success in the inhibition of tumor growth, the HAMA reaction has limited the use of these agents. Human recombinant antibodies offer a potential alternative and provide valuable clinical agents for cancer immunotherapy. Our aim was to produce a source of specific single chain antibodies (scFv) against HER2/neu and assess their effects on cancer cell line. Materials and Methods: A phage antibody display library of single chain Fv (scFv) was panned against three HER2/neu epitopes and differentiated by BstN1 fingerprinting. The selected clones were screened for the ability to bind the HER2/neu positive cell line (SKBR-3) by flowcytometry. The cell line was treated with 3 specific scFvs and the expression of HER2/neu transcript was measured by real time PCR. The effects of the selected scFv antibodies on the cell line were evaluated by MTT assay. Results: one specific clone was isolated against each epitope. Flowcytometry assay showed that the clones bound to HER2/neu expressing cell line with intensity range 75-80%. Real time PCR results revealed that scFv-II, -III and combination of all the three scFvs downregulated HER2/neu gene expression (Fig 1). All the single chain types alone and in combination significantly inhibited the proliferation of the SKBR-3 cells in the MTT proliferation assay (Fig 2).

Conclusion: Herceptin (Trastuzumab) is a humanized antibody against HER2/neu which is approved by the FDA for treatment of HER2/neu positive breast cancers. Researches have shown multiple life-threatening side effects of Herceptin on the patients and also the overall objective response rate to herceptin is only 15-20%. Therefore there is a need for development of an alternative. The human origin, small size (20-30kDa), rapid blood clearance and good tumor penetration of human scFvs offer potential advantages for the use of these agents in cancer immunotherapy. Our results suggest that the highly specific anti-HER2/neu human scFvs that inhibit the proliferation of the breast cancer cell line could contribute in breast cancer immunotargeting approaches. In vivo assessment of the antibodies is under investigation to show the therapeutic effects of the selected scFvs.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-04-03.
Abstract P5-05-06: The Role of Sprouty 2 in HER2 Signaling in Breast Cancer; Decreased Expression Is Associated with Poor Outcome Including in Trastuzumab-Treated Patients
Authors: Faratian D , Sims AH , Mullen P , Kay C , Um I , Langdon SP , Harrison DJ.
Published: April 2011

Purpose: Resistance to trastuzumab is a frequent clinical problem, in part due to the overriding activation state of the MAPK/PI3K signaling pathways. Sprouty-family proteins are negative regulators of MAPK/PI3K signaling, but their role in HER2 signaling and resistance to therapy is unknown.

Experimental design: The association of Sprouty 2 gene expression with grade, HER2-status, and survival was investigated in a meta-analysis of 1107 breast tumors from six published microarray studies. Sprouty regulation in response to HER2/HER3 signaling was studied using qRT-PCR. Changes in expression of Spry2 and feedback inhibition on trastuzumab-resistance were studied using full-length/dominant-negative transfection or chemical inhibition in SKBr3 and BT474 cell lines in cell viability assays. Finally, expression of Spry2 was measured in a cohort of 122 patients treated with trastuzumab by quantitative fluorescence microscopy (AQUA).

Results: Low Spry2 gene expression was associated with high HER2 protein expression. Spry2 was regulated through HER2/HER3 signaling as a delayed early gene, an effect reversed by treatment with the dimerization inhibitor pertuzumab. Overexpression of Spry2 in the SKBr3 trastuzumab-resistant cell line resulted in synergistic inhibition of cell viability with trastuzumab. Restitution of feedback inhibition with the PI3K-inhibitor LY294002 had a similar effect. Low Spry2 expression was associated with increased risk of death (HR = 2.28, 95% CI 1.22 - 4.26; p=0.008) in trastuzumab-treated patients, including in multivariate analysis (Cox regression analysis, p=0.002).

Conclusions: These results suggest that combinations of negative regulators of growth factor signaling may be an effective therapeutic strategy in breast cancers with deficient feedback inhibition.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-06.
Abstract P5-05-10: EIA-Induced PP2A Expression Prevents β-Trcp Mediated FOXO3a Degradation and Enhances Chemosensitization by Inhibiting TAK1/IKK Signaling
Authors: Chang Y-W , Su J-L , Hung M-C.
Published: April 2011

Background: E1A gene therapy was tested in multiple clinical trials in breast, ovarian, and head and neck cancers. E1A can sensitize paclitaxel-induced cell death and combined paclitaxel chemotherapy and E1A gene therapy is currently tested in a clinical trial for ovarian cancer patients. It has been shown that resistance to paclitaxel occurs in cells expressing low level of FOXO3a. We found that Forkhead box O-class (FOXO) transcription factor FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. Knocked down FOXO3a expression dramatically abolished E1A-induced chemosensitization of paclitaxel. E1A stabilized FOXO3a by preventing ubiquitin-dependent proteolysis. The E3 ligase involved in stabilizing FOXO3a is β-transducin repeat-containing proteins (ßTrCP); ßTrCP binding to FOXO3a requires phosphorylation of FOXO3a at Ser644 by IKKβ. E1A reduces βTrCP-mediated ubiquitination of FOXO3a by inhibiting IKKβ activity. Further, inhibited IKKß activity is due to E1A-induced expression of PP2A, which binds to transforming growth factor β-activated kinase 1 (TAK1), thus inhibiting TAK1's activation of IKKβ. In this study, we found that E1A stabilizes FOXO3a which is required to sensitize paclitaxel-induced apoptosis. The stabilization is achieved by E1A-induced expression of PP2A/C, which inhibits the binding of TAK1 to IKKβ, therefore abolishing IKKß's function in phosphorylating FOXO3a and FOXO3a degradation. This result provides a rationale for the combination of E1A gene therapy and paclitaxel chemotherapy and may also shed light on design of targeted therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-10.
Abstract P5-05-11: The Cellular Impact of HuR (Human (Hu) Antigen R) in Breast Cancer Cells on the Growth and Invasion In Vitro and the Expression of Cyclin D1 and MMP-9
Authors: Yuan Z , Sanders AJ , Ye L , Wang Y , Jiang WG.
Published: April 2011

Introduction: HuR, a ubiquitously expressed member of the Hu family, selectively binds and stabilizes ARE-containing mRNAs encoding proto-oncogenes, cell cycle regulators, cytokines and growth factors. The role of HuR and its cellular function in breast cancer remains unclear. In the present study, we aimed to provide new insights into the molecular and cellular implication of HuR in breast cancer.

Materials and methods. We first constructed a set of anti-HuR ribozyme transgenes that targeted human HuR. Breast cancer cells were transfected with the transgene, in order to establish new sublines with HuR expression knocked down. Cell growth and invasiveness were investigated using in vitro cell models. The expression of cyclin-D1 and MMP2 were determined using immunocytochemistry, Western blotting and polymerase chain reaction.

Results: Here, we show that MCF7 and MDA-MB-231 cells breast cancer cells stability transfected with a hammerhead ribozyme transgene specifically targeted to HuR (MCF7HuRKO and MDA-MB-231HuRKO) have a reduction in HuR expression both at mRNA and protein levels. Using these new sublines of breast cancer cells, the in vitro growth was evaluated. We showed that that HuR knockdown dramatically reduced cell growth in MCF7 cells (P < 0.001) and to a lesser degree reduced that in MDA MB 231 cells. We further demonstrated that reduction of HuR in MDA MB 231 cells (MDA-MB-231HuRKO) resulted in a significant reduction of the in vitro invasiveness in MDA-MB-231 cells (P < 0.001), although the same failed to occur to MCF-7 cells. Furthermore, we found that the decreased cell growth rate in MCF7 cells following HuR knockdown was seen together with a reduction in cyclin D1 transcript and protein levels. It was also interest to observe that the change in invasiveness in MDA-MB-231 cells after HuR knockdown was accompanied by a decrease in MMP-9 levels.

Conclusion: Our study shows that targeting HuR can influences breast cancer cell growth and invasion and suggests a role for HuR in vitro in enhancing breast cancer cell growth and invasion. These changes may be facilitated through changes in the level of cyclin D1 and MMP-9.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-11.