bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-06-01: MTA2 and AR Overexpression in ER-Negative Breast Cancer Cells: Roles in Invasion and Metastasis
Authors: Morales SF , Covington KR , Ciupek A , Brusco L , Weigel NL , Lu Y , Mills G , Fuqua SAW.
Published: April 2011

Background: We have previously shown that overexpression of metastasis associated protein 2 (MTA2) can render estrogen receptor (ER)-positive breast cancer cells hormone-independent through postranscriptional effects on ER acetylation and phosphorylation. Recently we discovered that MTA2 overexpression in ER-negative MDA-MB-231 breast cancer cells enhances invasion and metastasis in athymic nude mice which involves activation of the Rho pathway. It is also known that the androgen receptor (AR) is frequently expressed in breast tumors; however its role in proliferation, invasion, or breast cancer metastasis is poorly understood. Materials and Methods: MTA2 was stably overexpressed in MDA-MB-231 and its levels validated using Western blot analysis. To identify downstream effects due to MTA2 overexpression, we employed reverse phase protein arrays, and Affymetrix expression arrays. Significant changes in gene expression were identified using dCHIP software, and student t tests. Invasion was examined using modified Boyden chamber growth assays, proliferation was assayed using soft agar growth and MTT assays, and metastasis was measured as tumor growth in athymic nude mice. Results: MTA2 overexpression in ER-negative cells enhanced distant and skin metastases in athymic nude mice. In an attempt to identify effectors of MTA2-mediated metastasis, we used RNA microarray and protein array screens, and found that AR was significantly increased. As a control, we employed a rescue of the highly metastatic MTA2-MDA-MB-231 cell phenotype via stable transfection and add-back of Rho GDIa, a gene that was concomitantly down-regulated with MTA2 overexpression. AR levels were significantly reduced with Rho GDIa add-back. To determine if AR was functional in these cells, we used ARE-luciferase reporter assays and discovered that both basal, and agonist (R1881)-induced transcriptional activity were significantly enhanced. The AR antagonist, bicalutamide, was effective at significantly decreasing the invasive potential of MTA2- overexpressing MDA-MB-231 cells In vivo experiments in nude mice with bicalutamide treatment are underway.

Discussion: AR was significantly overexpressed with the aggressive phenotype conferred via MTA2 overexpression. This suggests that blockade of AR action might provide a new therapeutic target to inhibit metastasis of breast cancer cells.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-01.
Abstract P5-06-10: ErbB Signaling Is Required for Activation of Phosphatidylinositol-3 Kinase and Transformation of Mammary Epithelial Cells by Polyomavirus Middle T Antigen
Authors: Cook RS , Rinehart C , Garrett J , Chakravarti A , Arteaga CL.
Published: April 2011

Summary

Polyomavirus middle T (PyVmT) transforms cells through phosphatidylinositol 3-kinase (PI3K). Overexpression of ErbB2/ErbB3 heterodimers, potent activators of PI3K, occurs in PyVmT-driven mouse mammary tumors, but without known cause and consequence. Inhibition of ErbB2 with lapatinib, or genetically engineered loss of ErbB3, decreased PI3K signaling and tumor growth in mice, suggesting ErbB2/ErbB3 is required by PyVmT. ErbB2/ErbB3 formed signaling complexes containing PyVmT, p85 and Src. EZN-3920, a novel high-affinity oligonucleotide targeting ErbB3 transcripts, impaired ErbB3 expression in vivo, decreased PI3K signaling, cell survival, and growth of tumors, and improved response to lapatinib. Therefore, PyVmT utilizes ErbB2/ErbB3 overexpression to drive PI3K signaling. Furthermore, the challenge of ErbB3 as a kinase-inactive therapeutic target can be overcome by targeting ErbB3 mRNA transcripts in vivo. Significance

Given the widespread use of, and knowledge gained from the MMTV-PyVmT transgenic mouse breast cancer model, understanding how PyVmT utilizes existing cell signaling programs is necessary to interpret how results impact our understanding/treatment of human breast cancers. We found that ErbB2/ErbB3 heterodimers were a necessary part of PyVmT signaling complexes involving Src and PI3K, and that PyVmT depends on ErbB3 in the breast epithelium for PI3K activity and tumor growth. Because ErbB3 harbors a weak/inactive tyrosine kinase, therapeutic anti-ErbB3 interventions present with challenges. Further, anti-ErbB3 antibodies that block ligand interaction with ErbB3 do not alter ligand-independent ErbB3 signaling. However. these challenges were overcome using high-affinity oligonucleotides targeting ErbB3 mRNA. Use of the oligonucleotide EZN-3920 effectively reduced ErbB3 expression, inhibited PyVmT tumor growth, and improved the response of tumors to lapatinib. These results support oligonucleotide knock-down of targets as potential therapeutic strategy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-10.
Abstract P5-10-01: Overall Survival in Breast Cancer Patients in Randomized Controlled Trials Comparing Primary G-CSF Chemotherapy Support to Control
Authors: Lyman GH , Kuderer NM , Crawford J , Culakova E , Poniewierski MS , Huang M , Dale DC.
Published: April 2011

Background Randomized controlled trials (RCTs) have demonstrated that granulocyte colony-stimulating factor (G-CSF) is capable of reducing the risk of neutropenic complications including febrile neutropenia as wellas infection-and treatment-related mortality (Kuderer et al. JCO 2007). To address the potential impact of G-CSF support of chemotherapy on overall survival in patients with breast cancer, a systematic review of RCTs of chemotherapy with or without G-CSF support and at least 2 years of follow-up was conducted.

Methods A systematic review of the medical literature identified 20 RCTs of breast cancer patients receiving chemotherapy with or without primary G-CSF support and reporting overall mortality by study arm. Data extraction from eligible studies was undertaken by two independent reviewers. Heterogeneity was assessed by Cochran's Q-statistic and the Inconsistency Index (I2). Weighted summary estimates of relative risk (RR) with 95% CIs were based on the method of Mantel and Haenszel using a fixed effects model. Planned chemotherapy relative dose intensity (RDI) with G-CSF support compared to control was meta-regressed on the natural logarithm of the RR for mortality. Publication bias was assessed on the basis of Egger's regression intercept.

Results Patients in 20 eligible RCTs received chemotherapy with (n=5,938) or without (n=6,627) primary G-CSF support. Deaths were reported in 1,468 patients randomized to receive primary G-CSF and in 1,607 controls. No significant heterogeneity was observed (Q=23.53, P=.215; I2=19%). Overall RR for mortality was 0.94 [0.89-0.99; P=.029]. RR for mortality was 0.92 [0.85-0.99; P=.036] in the 11 trials of patients with locoregional disease compared to 0.98 [0.92-1.04; P=.503] in the 9 RCTs of patients with advanced disease. A nonsignificant trend was observed between median duration of follow up and RR reduction for mortality [P=.08]. A significant inverse trend was observed between chemotherapy RDI with G-CSF support and RR reduction for mortality [P=.05]. The greatest reduction in mortality was observed in the four RCTs of dose dense chemotherapy. A trend toward publication bias was observed among studies of patients with advanced disease but not locoregional disease.

Conclusions Overall mortality in patients with breast cancer is reduced in those receiving chemotherapy with primary G-CSF support compared to controls. Greater impact on mortality was observed in clinical trials of early-stage disease and in studies with greater chemotherapy RDI including dose dense schedules.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-01.
Abstract P5-10-04: Amplification of Topoisomerase 2 Alpha (TOP2A) in HER2/neu Negative Breast Cancer
Authors: Glynn RW , Mahon S , Miller N , Callagy G , Kerin MJ.
Published: April 2011

Background: TOP2A is of particular interest in breast cancer because of its association with response to anthracycline-based chemotherapies. Much of the work which has examined levels of TOP2A has concluded that amplification is restricted to those who are also HER2/neu amplified, leading some commentators to conclude that HER2/neu negative patients should not receive anthracyclines as part of their treatment. A couple of studies have identified TOP2A alterations in the absence of that of HER2/neu however, and the relationship between these targets needs to be better defined. We aimed to investigate the relationship between HER2/neu and TOP2A, whilst elucidating their association with clinicopathological variables thereby providing further insight into which patients are most amenable to anthracycline-based regimens.

Materials and Methods: Hierarchical clustering was performed on a 20 patient cDNA microarray to identify gene clusters of clinicopathological interest. RQ-PCR was then performed (n=96) to further assess gene amplification, and levels were determined using the comparative Ct approach & Taqman assays. An IHC microarray (n=76) was then employed to check for correlation between gene amplification and protein expression levels.

Results: Amplification levels of TOP2A did not differ significantly according to HER2/neu status by either cDNA microarray (p=0.623), RQ-PCR (p=0.475) or IHC microarray (p=0.736). By RQ-PCR, 14/48 (29.1%) of the HER2/neu negative patients demonstrated levels of TOP2A above the third quartile. Similarly, 11/48 (22.9%) of the HER2/neu positive patients returned values in the first quartile, thereby indicating low-level amplification. Of 60 patients characterised as HER2/neu negative using IHC and FISH, 14 (22.9%) were classified as TOP2A positive on the IHC microarray. Of the 14 patients deemed HER2/neu positive using IHC and FISH, meanwhile, the majority (n=10) were classified as TOP2A positive.

Discussion: Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER2/neu positive, and suggest that a significant proportion of HER2/neu negative patients exhibit high levels of TOP2A. These findings were not expected, are contrary to popular opinion, and have significant implications in the rationalisation of anthracycline-based therapies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-04.
Abstract P5-10-10: Benefit of Adjuvant Chemotherapy in Luminal A Breast Cancers
Authors: Heneghan HM , McDermott A , Malone C , McLaughlin R , Sweeney KJ , Kerin MJ.
Published: April 2011

Background:

Perou and Serlie's molecular portraits of breast tumors explain the phenotypic heterogeneity of breast cancers by demonstrating diversity in gene expression, and classify tumors into 5 unique subgroups. The commonest breast cancer intrinsic subtype, Luminal A (ER/PR+, HER2-), generally carries a good prognosis with lower incidence of metastatic spread and longer disease free and overall survival compared to non-luminal tumors. Yet within the Luminal A subgroup there appears to be heterogeneous outcome; and debate continues as to the need for adjuvant chemotherapy within this cohort. In the absence of validated molecular predictors of response to chemotherapy, we aimed to assess the outcomes of a large cohort of Luminal A breast cancer patients in order to determine prognostic factors which may guide future treatment strategies for this subgroup.

Methods:

1355 breast cancer patients treated in a tertiary referral symptomatic breast cancer unit, with known molecular subtype, were identified. 965 had Luminal A primary breast tumors, of whom 57% had received adjuvant chemotherapy. Clinicopathological details of all patients were reviewed, including particular details of the chemotherapeutic regimens administered. Current outcome in terms of disease-free (DFS) and overall survival (OS) was determined. Kaplan-Meir & multivariate analyses were performed to identify tumor/patient characteristics indicative of poor response to adjuvant chemotherapy.

Results:

Mean follow-up was 61.3 months. Overall & disease free survival were significantly better for those who received adjuvant chemotherapy (Mean OS: 60 vs. 54 months, p=0.051. DFS: 54 vs. 44 months, P<0.001). Patients whose disease progressed despite chemotherapy had poorer prognostic indicators at the time of diagnosis, compared to their Luminal A counterparts who remained disease free: including significantly greater tumor size (30.34mm vs. 25.0mm, p=0.01), 69% were node positive and 59.4% had stage 3 or 4 disease (chi square<0.001). Of the cohort of Luminal A patients who remained disease free throughout follow-up, 40% had not received adjuvant chemotherapy. Those women who remained disease free despite not receiving systemic chemotherapy had smaller tumors (26mm vs. 31 mm, p=0.021) were generally postmenopausal (80% vs. 56%, P<0.001) and had predominantly node negative (59% vs. 37%, P<0.001) early stage I and II disease (78% vs. 73%, p=0.001), compared to those surviving women who did get chemotherapy.

Conclusion:

Adjuvant chemotherapy is beneficial in the cohort of Luminal A's with advanced disease at diagnosis. However it is critically importance to identify this particular subgroup & spare those with early disease the toxicity of treatment from which they are unlikely to derive further benefit.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-10.
Abstract P5-10-16: Iodine/Anthracyclines Is the Best Combination Against Mammary Cancer. Antineoplastic Synergism and Cardioprotection
Authors: Alfaro Y , Delgado G , Aceves C.
Published: April 2011

Mammary cancer is the world's most common malignant neoplasia for women. Recently, the mortality for breast cancer has fallen due principally to early detection and to use of neoadjuvant chemotherapy. Anthracycline antibiotics are the most commonly used anticancer drugs, and Doxorubicin (DOX) is the first choice to treat mammary cancer. Nevertheless, its use has limited by its cadiotoxic side effects, which are generated by free radicals. Our studies in methylnitrosourea (MNU)-induced mammary cancer models have shown that supplementation with moderately high doses of molecular iodine (I2) exhibits two distinctive and beneficial effects: antineoplastic and antioxidant. In the present work we explored these dual characteristic of I2 (0.05%) as an adjuvant to DOX16 (therapeutic dose of 16 mg/kg) and DOX8 (8 mg/kg) in female Sprague Dawley rats (200 g) with tumors induced by a single dose of 50 mg MNU per Kg. Iodine intake is initiated 2 days before DOX application and continues up to sacrifice 7 days later. The following parameters were registered: body weight, tumor size, tumor proliferation rate (proliferating cell nuclear antigen, PCNA), serum creatinine kinase-MB activity (CK-MB), cardiac lipoperoxidation (cLPO), and cardiac catalase activity (cCAT). Values correspond to mean± SD. Different superscripts represent significant (p≥0.05). Tumor reduction was greater in the DOX16 + I2 group than in the DOX 16 group (75% vs. 50%, respectively), and was associated with a significantly greater decrease in the rate of tumor cell proliferation (25% vs 10% decrease in PCNA-positive cells), showing the synergistic effect of I2. In contrast, at both DOX doses, the DOX + I2, groups had lower body weight loss and less cardiac damage (CK-MB; 280% vs 100%, cLPO 100% vs 0%) than with DOX alone. cCAT was not changed by any of the treatments.Conclusions: Iodine acts as an adjuvant by significantly enhancing the antiproliferative effect of DOX at a therapeutic dose (DOX16), and it exerts significant general and cardiac protective effects that do not involve catalase activation. Cellular and molecular mechanisms involved in these dual effects of iodine are currently being analyzed. The authors thank Drs. Mauricio Diaz, Marcela Lizano, and Brenda Anguiano as well as Biol. Felipe Ortiz for their technical assistance and Leonor Casanova for academic supports. We also thank Dr. Dorothy Pless for proof-reading. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955 and 47928/47928. Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-16.
Abstract P5-11-02: The Carry-Over Effect of Adjuvant Zoledronic Acid: Comparison of 48- and 62-Month Analyses of ABCSG-12 Suggests That the Benefits of Combining Zoledronic Acid with Adjuvant Endocrine Therapy Persist Long after Completion of Therapy
Authors: Gnant M , Mlineritsch B , Stoeger H , Luschin-Ebengreuth G , Heck D , Steger G , Jakesz R , Singer C , Eidtmann H , Greil R.
Published: April 2011

Background: ABCSG-12 examined the efficacy of ovarian suppression using goserelin combined with tamoxifen (TAM) or anastrozole (ANA) ± zoledronic acid (ZOL) in premenopausal patients with endocrine-responsive early breast cancer. Results at 48 months and at 62 months show that adding ZOL significantly improved disease-free survival (DFS) and reduced disease recurrence.

Methods: Premenopausal patients with endocrine-responsive early breast cancer (N = 1,803) were randomized to goserelin (3.6 mg q28d) and TAM (20 mg/d) or ANA (1 mg/d) ± ZOL (4 mg q6mo) for 3 years. Endpoints included DFS and overall survival, both analyzed using log-rank test and Cox models.

Results: At 48 months’ median follow-up, ZOL significantly reduced the risk of DFS events by 36% versus no-ZOL (hazard ratio [HR] = 0.64; P = .01); this was maintained at 62 months’ follow-up (HR = 0.68; P = .009). In addition, the trend toward reduced risk of death with ZOL was maintained at both 48 months (HR = 0.60; P = .11) and 62 months (HR = 0.66; P = .10) compared with no-ZOL. Patients receiving ZOL also had fewer distant recurrences compared with no-ZOL: 29 versus 41 events at 48 months, and 44 versus 56 events at 62 months. No significant renal adverse events or confirmed cases of osteonecrosis of the jaw (ONJ) have been reported.

Conclusions: Comparisons of 48- and 62-month data suggest a possible carry-over of the ZOL anticancer benefit 2 years after treatment completion. Additional analyses will be presented, including disease outcomes during therapy and after treatment, as well as overall survival analyses.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-02.
Abstract P5-11-06: Impact of Educational Material on Compliance and Persistence Rates with Adjuvant Aromatase Inhibitors: First Year Data in Patients Recruited in France (CARIATIDE STUDY)
Authors: Serin D , Clippe S , Resbeut M , Radji A , Jovenin N , Benoit C , Spaeth D , Puyuelo L , Jaubert D , Cowen D , Ferrero J-M , Marty M , Buyse M , El Amiri H , Piedbois P.
Published: April 2011

Rationale: Issues have been reported with aromatase inhibitors (AI) compliance in adjuvant breast cancer. The present study was performed in order to better assess patient (pt) compliance, and to test whether educational material (EM) can improve compliance rate. Methods: This 2-year observational study (NCT00681122) was conducted on 2,758 patients in 18 countries, and completed in March 2009. Pts were allocated to Standard Therapy AI (anastrozole or letrozole), Group A, or to Standard Therapy + EM (Group B) following a 1:1 randomisation. EM consisted of a range of information on breast cancer-related topics. Primary endpoint was compliance rate for AI: patient is defined as being compliant if she took more than 80% of her tablets during the last year. Secondary endpoints were: persistence rate at 1 and 2 years (patient is classified as a persistent user of adjuvant AI medication when the data supports the persistent intake of adjuvant AI medication during the one-year period), and reasons for and time to AI discontinuation. Specialised questionnaires were used to evaluate pt compliance and behaviour (EORTC-INPATSAT-32, OPTIMA-X, GHQ-12, FACT-ES, compliance questionnaire and EM feedback in Group B).Results: 711 pts were randomised in France, 348 in Groupe A and 363 in Groupe B. Pt characteristics were well balanced across randomised arms. Mean age was 65 years, mean BMI was 26, 20% of pts had received hormone replacement therapy, and 68% had associated co-morbidities, including musculoskeletal disorders in 12%. Preliminary analysis showed that compliance rate at 1 year was only 74%, with no difference between the 2 groups (73% in Group A vs. 74% in Group B).

Persistence rates were also similar (77% vs.78%). AI discontinuations were mainly attributed to AI related side effects. Prognostic factor analysis showed no baseline characteristics associated with compliance behaviours.Conclusion: At 1 year, Cariatide preliminary analysis showed that compliance rate of adjuvant AI in France does not exceed 74%, and is not improved by EM.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-06.
Abstract P5-11-13: Tamoxifen and Ovarian Function
Authors: Berliere M , Dalenc F , Piquard N , Leconte I , Fellah L , Baurain J-F , Galant C , Duhoux F , Machiels J-P.
Published: April 2011

Background: to study and compare ovarian function (clinical and biological data) among premenopausal breast cancer patients receiving tamoxifen alone (group I) or tamoxifen following chemotherapy (group II), because some studies suggest that amenorrhea is an insufficient parameter to define menopausal status.

Material and methods: between 1999 and 2003, 138 premenopausal patients, treated for early breast cancer, were included: 68 patients in the group of tamoxifen alone and 70 patients in de group of tamoxifen administered after chemotherapy (6 cycles of FEC 100 on day 1 every 3 weeks -5 fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2- or 4 cycles of EC on day 1 every 3 weeks -epiadriamycine 75 mg/m2, cyclophosphamide 500 mg/m2-). All patients had a confirmed premenopausal status (biological data) at the entry of the study. The median age in group I was 44.5 (36 to 48) and 42 in group II (35 to 47.5). In group I, all were stage I and in group II, 34 were stage I and 36 were stage II. They were followed prospectively every 3 months for 3 years: date about menses, physical examination and blood tests (LH, FSH, 17-bêta-estradiol). Vaginal echography was added every 6 months. After 3 years, prospective evaluation was closed. Retrospective evaluation of all data was performed in 2009.

Results: three patients were out of study in the group I and 2 were out of study in the group II. According to clinical data, patients were devided in 4 subgroups:

a: regular menses (≥10 cycles/year) b: spaniomenorrhea (5 to 9 cycles/year) c: severe spaniomenorrhea (1 to 4 cycles/year) d: complete amenorrhea.

The number of patients in each subgroup is respectively:

- For group I (65 patients): 3 (4%), 19 (29%), 38 (58%) and 5 (8%).

- For group II (68 patients): 2 (3%), 21 (30%), 38 (55%) and 7 (10%). The most interesting parameter to be studied wass the estradiol levels.

Median values of estrogen levels

For patients of subgroup a, tamoxifen mimicked an ovulatory cycle such as observed in patients receiving citrate of clomifen. For patients of subgroup b, the variations corresponded to nearly a normal ovulatory cycle. For patients of subgroups c and d, tamoxifen induced low levels of estradiol, LH and FSH, and very few variations. Estrogen levels did not to seem have an impact on disease free survival rate after 3 years of follow-up (100% in group I and 98.6% in group II and after 5 years (98.5% and 97%). In the two groups I and II, estrogen levels from patients of subgroups a and b were significantly higher than in subgroups c and d (p < 0.001). Conclusion: amenorrhea is an insufficient parameter to define menopausal status of patients receiving tamoxifen. Low estradiol level must be coupled to other biological parameters to characterize endocrine status. These data are very important in the choice of endocrine therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-13.
Abstract P5-12-02: Long Term Cardiac Toxicity after Adjuvant Trastuzumab for Early Breast Cancer: Implications for Life-Expectancy and Cost-Effectiveness
Authors: Hall PS , McCabe C , Plummer CJ , Cameron DA.
Published: April 2011

Introduction: Trastuzumab has significantly improved survival outcomes for women with HER2 over-expressing early breast cancer. Observed short term cardiac toxicity appears reversible in the majority of cases and confidence in the long term safety is growing. Despite this, reported follow-up from adjuvant trastuzumab clinical trials does not extend beyond six years. If trastuzumab causes myocardial cell death with loss of cardiac reserve in addition to reversible myocardial stress alone, this may lead to an increased long term risk of congestive heart failure (CHF). The future incidence of this possible late cardiac toxicity remains uncertain. The aim of this study is to quantify the consequences of scenarios of late cardiac toxicity on the survival benefit and cost-effectiveness of adjuvant trastuzumab for women treated for HER2 over-expressing early breast cancer.

Methods: A cost-utility analysis was performed using a discrete-state time-dependent semi-Markov model to calculate expected costs and benefits over the lifetime of an average cohort of women with HER2 over-expressing early breast cancer when treated with or without one year of adjuvant trastuzumab. The perspective was the UK NHS. Scenarios across the full range of possibility were explored along with estimates based on expert opinion to determine the impact of possible long-term cardiac toxicity on life-expectancy, quality of life and treatment costs. Probabilistic sensitivity analysis was used to characterise uncertainly around expected outcomes.

Results: With a willingness-to-pay threshold of £30,000 (GBP) per quality adjusted life-year, trastuzumab is cost-effective if the lifetime increased risk of CHF is no more than three times the average level expected in an anthracycline treated population of women diagnosed with HER2 overexpressing early breast cancer (figure 1). Life-expectancy gains from using adjuvant trastuzumab persist even if there is a high consequent lifetime risk of congestive cardiac failure (figure 2). Conclusion: The use of adjuvant trastuzumab remains the optimal clinical and economic treatment strategy even if its use leads to moderately increased levels of cardiac disease in later life. This study supports current confidence in its cost-effectiveness and safety. Long-term follow-up after current and future adjuvant breast cancer trials is essential in to reduce the uncertainty around these estimates.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-12-02.
Abstract P5-13-08: Factors Affecting Delivery of Planned Chemotherapy for Breast Cancer in Older Women
Authors: Ngamphaiboon N , Edge SB , Groman A , Wilding GE , Ademuyiwa F , Levine EG , Watroba N , O'Connor TL.
Published: April 2011

Background: Recent studies suggest that older women derive the same benefits from adjuvant systemic chemotherapy (AST) as younger women. In older women, the ability to successfully complete chemotherapy may be complicated by other health conditions and performance status. This study examines the frequency of inability to complete planned AST and factors associated with difficulty administering AST in older women.

Methods: We performed a retrospective analysis of breast cancer patients (age≥65) who received adjuvant/neoadjuvant chemotherapy at Roswell Park Cancer Institute from 9/1997 to 1/2010. Endpoints considered collectively as “difficulty “ in delivering AST were delay in treatment, hospitalization, dose reduction and discontinuation of AST. Factors defined a priori that could affect these outcomes were creatinine clearance (CCr), obesity (BMI ≥30), cardiac disease, hypertension, psychiatric disorders, diabetes, cerebrovascular disease, previous malignancy, COPD/asthma, Charlson comorbidity index, and use of anthracycline-based chemotherapy. The Pearson chi-squared test was used to identify the significant categorical factors associated with each of the five binary responses indicating difficulty administering AST. Logistic regression was used to obtain crude and adjusted odds ratios to further examine the relationships. Kaplan-Meier methods were used to estimate survival distributions, progression free and overall survival. The log-rank test was used for comparison between women experiencing difficulty with treatment and those with no difficulty with treatment. A 0.05 nominal significance level was used in all testing. Statistical analysis and plots were completed using SAS, version 9.2, statistical software (SAS Institute Inc., Cary, NC).

Results: 193 women age 65 and over received AST (median age of 70 years - range 65-86). Median follow up was 40.9 months. 73% received anthracycline-based AST. Factors associated with difficulty, delay, dose reduction, hospitalization, or failure to complete planned AST are shown in the Table. Women who completed planned AST had better OS than those who did not complete AST (p=0.01). Women who completed therapy with difficulty had no difference in outcome compared to those without difficulty [DFS (p=0.07) and OS (p=0.18)].

Conclusions: Age, cardiac disease, diabetes, hypertension, CCr, obesity, CCI, and sum of comorbidity significantly impact the ability to deliver and complete AST in older women with BC. Completing planned chemotherapy is associated with improved survival.

Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-08.
Abstract P5-14-06: Relationship between Surgery and Survival in Elderly Breast Cancer Patients over 75 Years of Age
Authors: Dordea M , Jones R , Pujol Nicolas A , Sar S , Batson S , Fetherston A , Truran P , John S , Iwuchukwu O.
Published: April 2011

Background: There is an increasing interest in the reporting of breast cancer characteristics, treatment and survival in the elderly age group (>75). Studies suggest that elderly women receive less aggressive treatment, experience higher disease progression and mortality from breast cancer. We report on a single institutional experience of 256 consecutive cases of symptomatic breast cancer in a population of over 75 years of age. Methods: We undertook a retrospective review of 256 consecutive cases of breast cancer in patients over the age of 75 treated at the Sunderland Royal Hospital between August 1998 and August 2005. Therapeutic/surgical decision was a joint affair involving our multidisciplinary team, the patient and her family. Patient demographic data, tumour biology data, therapeutic data and outcome data were recorded. Statistical analysis was performed by the Newcastle Industrial Statistics Unit. Results: 142/256 patients underwent surgical intervention, 114/256 did not. Mean follow up was 6.4 years. The findings as well and their statistical significance are illustrated below:

Physiological reserve, treatment and outcomes

Table 1

Our results show a weak but statistically significant association between surgery and survival (p=0.05, CI 0.00046 - 0.19641) and a strong statistically significant association between surgery and disease progression/recurrence (p=0.001, CI 0.08713 - 0.03145). The morbidity of our surgical group is low. We experienced one postoperative death.

Discussion: We are cautious in affirming that our elderly group suffers from under treatment. There may be reasons for the observed pattern. Apart from a discrepancy in our axillary staging procedures (15/142), all suitable patients received adjuvant radiotherapy. Adjuvant chemotherapy was omitted in most cases, however this may be the result of multidisciplinary decisions guided by AdjuvantOnline calculations and patient's wishes. Women in the group treated conservatively are significantly less fit hence suffering high cancer unrelated mortality. As a consequence of their unfitstate the elderly group (treated conservatively) suffers higher disease related progression and mortality.

Overall, in our retrospective study surgical treatment with adjuvant endocrine and/or radiotherapy was associated with a statistically significant advantage in terms of disease related mortality and local disease control. We suggest that treatment pathways should be guided by physiological reserve and geriatric assessment tools rather than age alone.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-06.
Abstract P5-15-03: Patient Characteristics and Clinical Outcome of Patients with Secondary Inflammatory Breast Cancer. M.D. Anderson Cancer Center, Retrospective Review
Authors: Alvarez RH , Cristofanilli M , Hsu L , Ueno NT , Alizadeh PA , Lucci A , Reuben JM , Buchholz TA , Hortobagyi GN , Valero V.
Published: April 2011

Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer accounting for 1 to 5% of all breast cancers (BC). Secondary inflammatory breast cancer (S-IBC) is the development of inflammatory breast cancer clinical featurs such erythema, edema or skin changes that mimic IBC in either a breast that already had cancer or contralateral previously unaffected breast. (Dawood S, 2008). Currently there are sparse available data to help determine whether S-IBC differs from the P-IBC. The purpose of this analysis was to evaluate the clinical outcomes of pts with S-IBC.

Methods: This is a retrospective analysis from prospective M.D. Anderson Cancer Center (MDACC) database that includes 522 pts with P-IBC and 44 pts (8.5%) with S-IBC treated between 1988 and 2009 at MDACC.

Results: Median age of the S-IBC pts was 54 years (range 25-75); 33 pts (75%) were postmenopausal; 21 pts (47.7%) had hormone-receptor negative and 9 pts (20.5%) HER-2/neu-amplified. 32 pts (72.7%) had S-IBC stage III and 12 pts (27.3%) stage IV disease. The median interval to develop S-IBC from the primary BC was 147 months (mo) (range 4-310). In a cohort of 13 pts with primary BC who received no radiation therapy (RT) all (100%) pts developed S-IBC in the contralateral breast. Among the 33 pts with primary BC who received RT, 13 pts developed ipsilateral S-IBC whereas the remaining 20 pts developed contralateral S-IBC (p = 0.013). Comparing the S-IBC cohort with the P-IBC cohort, we found the rate of pCR to be higher in P-IBC than in S-IBC (13.6% vs. 3.1%; p = 0.09). Both cohorts had similar distribution in race, menopausal status, hormone-receptor and, HER2 status, and nuclear grade. Moreover, the median PFS was 28.4 mo vs. 22.1 mo. for P-IBC and S-IBC, respectively (p = 0.31). The median OS was 59.5 mo and 53.2 mo for P-IBC and S-IBC, respectively (p = 0.17). In a Cox multivariate analysis of the S-IBC cohort, after adjusting for age, ER/PR-status, LVI, nuclear grade and pCR, HER2/neu-amplified disease was associated with shorter RFS (HR 2.19; CI 0.87-5.50; p = 0.001) and the ER-positive group was associated with a marginal increase in overall survival (HR 0.18; CI 0.03-1.02; p = 0.05). Conclusion: In this retrospective analysis, S-IBC was associated with a lower rate of pCR but with similar RFS and OS compared with P-IBC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-15-03.
Abstract P5-15-06: Evaluation of Treatment of Primary Early Breast Cancer in the Elderly
Authors: Visser RPJ , Faneyte IF , Heymans HJ , Kouwenhoven EA.
Published: April 2011

Background: National guidelines for treatment of breast cancer are not applicable for the frail elderly. Treatment should be individualized for these patients.

Aim: Evaluation of treatment of the elderly (aged 70+) patient with primary early breast cancer: breast conservative surgery (BCS), guideline adherence and differences in (all cause and cancer specific) mortality risk and survival.

Materials and Methods: female patients with stage cT1-2N0-1 primary breast cancer, diagnosed from January 2002 - December 2008 were included in this retrospective analysis. Treatment was compared with national guidelines. Age categories were made for 80-plus, 70 to 80 and 70-minus. Differences in tumor biology and treatment were evaluated using X2- tests, differences in Hazard ratio using Cox-regression analysis and differences in survival using Kaplan-Meier analysis. Results: 1569 patients were included. Divided by age: 80 and up (n=148), 70 to 80 (n=256), 70 and below (n=1165). Median time of follow-up was 48 (1-99) months.

Tumor characteristics: there was no significant differences between patients aged 70 and up and below 70 for ER/PR status, Her2neu status, tumor grade and pathologic tumor size. There were significant differences for axillary lymph node involvement (pN0: 66,6% vs 56,6%, p=0,004) and tumor morphology (68,0% vs 77,8% ductal carcinoma, P<0,001). Comparison of treatment: 80+ vs 70-80 vs 70-, BCS: 29,6% vs 57,9% vs 55,7% (P<0,001 for 80+ vs 70-80), treatment according to guidelines: 38,9% vs 81,3% vs 93,3% (P<0,001 for 80+ vs 70-80 vs 70-), surgical treatment: 54,3% vs 96,1% vs 99,5% (P<0,001 for 80+ vs 70-80 vs 70-), radiotherapy following BCS: 56,5% vs 96,3% vs 98,4% (P<0,001 for 80+ vs 70-80), adjuvant systemic therapy when indicated: 73,2% vs 68,9% vs 90,1% (P<0,001 for 70-80 vs 70-).

Hazard Ratio for mortality: ages 80 and up: individualized vs guideline-adhered all cause HR = 1,903 (P<0,001). Cancer specific HR = 0,601 (p = 0,431). Ages 70-80: individualized vs guideline-adhered HR = 3,184 (p <0,001). Cancer specific HR = 2,842 (p = 0,083). 5-year all-cause survival: ages 70 and up vs 70-: 64% vs 91%, log rank P<0,001 (fig.1). 5-year cancer specific survival: ages 70 and up vs 70-: 91% vs 94%, log rank p = 0,064 (fig.2). Conclusion: Individualized treatment was frequent in elderly breast cancer patients, especially in patients aged 80 and up. While overall survival was significantly lower for septuagenarians, there was no significant difference in cancer specific mortality and survival.

Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-15-06.
Abstract P6-01-01: Risk of Invasive Breast Cancer and Ductal Carcinoma In-Situ in Women with Atypical Papillary Lesions of the Breast
Authors: Cuneo KC , Dash RC , Wilke LG , Koontz BF.
Published: April 2011

Background: Benign papillary lesions of the breast including papilloma and papillomatosis are believed to be associated with a low risk of developing breast cancer. The risk of breast cancer development in patients who have an atypical papilloma or who have a papilloma in conjunction with atypical hyperplasia is not well defined.

Methods: All patients who underwent a biopsy at Duke University Medical Center between October 1992 and December 2009 for a papillary lesion of the breast were identified. Patients were excluded if they had a previous or concurrent diagnosis of invasive or in-situ malignancy or less than 6 months of follow up. The remaining patients were analyzed to determine the risk of developing breast cancer.

Results: Median follow up for the 167 patients with a papillary lesion of the breast included in the analysis was 4.6 years. 51 patients had an atypical papillary lesion. 111 patients had atypical hyperplasia in conjunction with a papilloma. 35 patients had a papilloma without atypia or atypical hyperplasia. Patients with an atypical papilloma were more likely to develop an invasive or in-situ breast cancer with a 5 year actuarial risk of 13.0% (24 patients at risk) versus 4.6% (49 patients at risk) (p=0.03). Patients who had atypical hyperplasia in conjunction with a papilloma were also more likely to develop invasive or in-situ breast cancer with a 5 year actuarial risk of 9.8% (48 patients at risk) versus 0% (15 patients at risk) (p=0.05). In the group with an atypical papillary lesion, the actuarial risk of ipsilateral breast cancer or DCIS development was 8.2% at 5 years (24 patients at risk) and 21.1% at 10 years (12 patients at risk). In the group with atypical hyperplasia in conjunction with a papilloma, the actuarial risk of ipsilateral breast cancer development was 3.9% at 5 years (48 patients at risk) and 8.5% at 10 years (18 patients at risk). The majority of patients underwent an excisional biopsy for their papilloma (150 patients). Patients who had a core needle biopsy alone had a 5 year actuarial risk of ipsilateral breast cancer or DCIS of 15.3% versus 2.0% for patients who had an excisional biopsy (p=0.03). All of the patients who had only a core biopsy and later developed an ipsilateral cancer or in-situ disease had an atypical papilloma.

Discussion: Papillary lesions of the breast with atypical features may be associated with an increased risk of breast cancer and DCIS. Atypical papillary lesions should be fully excised or followed closely.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-01.
Abstract P6-01-02: Flat Epithelial Atypia of the Breast on Core Needle Biopsies — To Re-Excise or Not
Authors: Uzoaru I , Morgan BR
Published: April 2011

Flat epithelial atypia (FEA) of the breast have a tendency to calcify, and as such, are becoming increasingly detected by mammography. There is no consensus yet on whether to excise these lesions or not after diagnosis on core needle biopsies (CNB). We reviewed 3948 consecutive mammotome breast CNB from our surgical pathology files between June 2004 and June 2009 correlating histomorphologic, radiological, and clinical features. Diagnosis of FEA was made based on the 2003 WHO definition (replacement of native epithelial cells by a single layer of mildly atypical cells often with apical snouts, or proliferation of a monotonous atypical cell population in the form of stratification of uniform, cuboidal to columnar cells generally up to 3-5 cell layers with occasional mounding). There were145 (3.7%) cases of pure FEA and 58 (1.5%) cases of concomitant FEA and atypical ductal hyperplasia (ADH). In the pure FEA population, the age range was 33-82 years (median 49 years) and 67 patients (67.4%) had calcifications on mammography. There were 95 patients of the pure FEA group who underwent subsequent excisional biopsies with the following findings: Benign-19(20%), ADH-36(38%), Ductal carcinoma in situ (DCIS)-1(1.05%), DCIS and invasive ductal carcinoma (IDC)-2 (2.10%), atypical lobular hyperplasia (ALH)-3 (3.15%). In the concomitant FEA and ADH group, the age range was 34-83 years (median 51.50), and 50 patients (86.2%) had calcifications on radiograph. Of these, 44 patients underwent subsequent excisions with the following findings: Benign-10(22.7%), DCIS-4 (9.09%), DCIS and IDC-2(4.54%), DCIS+lobular carcinoma in situ (LCIS) + Invasive lobular carcinoma (ILC)-1(2.27%), papillary carcinoma-1(2.27%), and tubular carcinoma-1(2.27%). The incidence of carcinoma in the FEA+ADH group is about 20% (9 out 44) and 3% (3 out of 95) for the pure FEA group. This difference is statistically significant (p=0.0016). The relative risk of carcinoma findings in the ADH+FEA group versus the pure FEA group is 6.4773, 95% CI: [1.8432, 22.76 24]. These findings suggest that pure FEA in spite of having an association with carcinoma, albeit a low association, has a greater association with ADH, a well known risk factor for development of breast cancer. The contentious issue, however, still remains what to do with FEA when diagnosed by CNB since there is no consensus on the clinical management. Additional studies are needed to further understand the natural history of these lesions and provide a guide for their management.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-02.
Abstract P6-01-04: Ductal Carcinoma In-Situ Associated with Triple-Negative Invasive Breast Carcinoma Is Often Immunohistochemically Distinct from Invasive Component
Authors: Simon RA , Karim TA , Zhang C , Steinhoff MM , Sung CJ , Quddus MR.
Published: April 2011

Background: Gene expression profiling studies have identified a sub-set of breast carcinoma known as basal-like carcinoma, which characteristically do not express estrogen receptor (ER), progesterone receptor (PR), or HER2neu (HER2). These triple negative invasive ductal carcinomas (TN-IDC) are associated with an aggressive clinical course and poor prognosis. Little information exists in the literature concerning ductal carcinoma in-situ (DCIS) associated with TN-IDC. We evaluated the frequency, histologic features, and receptor status of DCIS associated with TN-IDC.

Design: From our institutional archives between July 2006 and August 2009, we retrieved all cases of intermediate and high grade invasive ductal breast carcinoma. Based on the immunoprofiling, invasive carcinomas were categorized into either TN-IDC or non triple-negative invasive carcinoma (non-TN-IDC). Immunohistochemistry for ER, PR, and HER2 was performed on the DCIS of the TN-IDC group and on some available cases from the non-TN-IDC group. The frequency, receptor status, and nuclear grade of DCIS associated with both groups were noted. Statistical analysis was performed using Fisher Exact Test. Results: Among a total of 224 cases, 56 (25%) were classified as TN-IDC and 168 (75%) as non-TN-IDC. DCIS was seen in 28 (50%) TN-IDC cases and in 150 (89.3%) non-TN-IDC cases (P<0.0001). Sufficient tumor was available for immunohistochemical staining in 23 of 28 cases with DCIS in the TN-IDC group. Within the 23 cases, the DCIS were triple negative in 15 cases (65%). Of the remaining 8 cases (35%), 4 were positive for ER and PR, but negative for HER2, while the other 4 cases were negative for ER and PR but positive for HER2. Ninety-six cases in the non-TN-IDC group had available immunostains for review, 7 of which (7.3%) displayed a different receptor status from their invasive counterparts (p=0.0016, compared with TN-IDC). Two cases of non-TN-IDC showed an associated TN-DCIS. Of the 28 cases of TN-IDC associated with DCIS, 4 (14.3%) showed lower nuclear grade in DCIS than in its invasive counterpart, compared with 22 of 150 (14.7%) non-TN-IDC cases (no significant difference). One TN-IDC case displayed two distinct morphologic patterns of DCIS; neither pattern was triple negative.

Conclusion: Our study demonstrated the presence of DCIS in a considerable proportion of TN-IDC although at a significantly lower frequency than in non-TN-IDC. DCIS associated with TN-IDC was significantly more likely to display a different immunoprofile from its invasive counterpart than DCIS associated with non-TN-IDC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-04.