bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-05-22: PI3K pathway as a novel target in androgen-driven aromatase inhibitor resistant breast cancer
Authors: Young Leonie S , Ali Azlena , Creevey Laura , Bane Fiona , Marzuki Wan Afif , Hill Arnold DK , McIlroy Marie 
Published: May 2015

Abstract
Breast cancer has the highest incidence and second highest mortality rate among all cancers in women worldwide (1). The gold standard treatment for post-menopausal breast cancer is aromatase inhibitor (AI) therapy. Unfortunately, resistance is inevitable in about 30-60% of these patients (2). Research from our lab has previously identified a transcription factor, HOXC11, to be associated with breast cancer resistance and metastases (3). Prosaposin (PSAP) was then identified as a putative HOXC11 target gene in the AI resistant setting. PSAP is a secreted protein that also plays a role in metastatic prostate cancer in both a ligand dependent and independent fashion (4,5).
We have previously shown PSAP to be an androgen responsive gene that can upregulate androgen receptor (AR) expression in a ligand dependent manner in AI resistance. An AR antagonist was effective at slowing down cell proliferation in AI resistant cells in vitro . However, since PSAP can also potentially act in a ligand independent fashion, this current study is focused on evaluating the role of PSAP in PI3K pathway activation in the development of AI resistance. Treatment of cells with recombinant PSAP protein (rhPSAP) resulted in increasing expression of p-AKT in a dose-dependent manner. To target this pathway of resistance, we used a pan-class PI3K/mTOR inhibitor BEZ235 on our AI resistant cells. Functional studies with BEZ235 treatment showed significant reduction in both cell motility as well as cell proliferation. Treatment of AI resistant cells with BEZ235 resulted in decreased expression of p-AKT, with little or no effect on AR expression. These findings suggest that to prevent resistance to AI therapy, combination treatment regimens including AR antagonists plus a PI3K inhibitor may ensure sustained response to therapy.
References:
1. Servick K. Breast Cancer: a World of Differences. Science Magazine. Special Issue. March 2014
2. Kazi AA et al. Breast Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer. Cancer Research. 2014; 16:R15
3. McIlroy M et al. Cancer Res.2010;70(4);1585-94
4. Koochekpour Set al. Prosaposin is an AR-target gene and its neurotrophic domain upregulates AR expression and activity in prostate stromal cells. J Cell Biochem. 2008; 104: 2272–2285.
5. Koochekpour S et al. Prosaposin is a novel androgen-regulated gene in prostate cancer cell line LNCaP. J Cell Biochem. 2007; 10: 631–641.
Citation Format: Leonie S Young, Azlena Ali, Laura Creevey, Fiona Bane, Wan Afif Marzuki, Arnold DK Hill, Marie McIlroy. PI3K pathway as a novel target in androgen-driven aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-22.
Abstract P3-06-13: Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy – The SpheroNEO study
Authors: Halfter Kathrin ML , Ditsch Nina , Kolberg Hans-Christian , Fischer Holger , Hauzenberger Tanja , Edler von Koch Franz , Bauerfeind Ingo , von Minckwitz Gunter , Funke Ilona , Crispin Alexander , Mayer Barbara 
Published: May 2015

Abstract
(1) PURPOSE
The aim of the prospective trial was to determine if cell survival in a breast cancer spheroid model following cytostatic treatment in vitro predicts treatment response in breast cancer patients receiving equivalent neoadjuvant therapy.
(2) PATIENTS AND METHODS
Three-dimensional spheroids were directly generated from fresh tumor biopsy samples of 78 patients eligible for neoadjuvant therapy. Cell survival in vitro, as well baseline clinical and pathological characteristics were correlated with the outcome following treatment of each patient to determine the factor(s) most highly associated with pathological complete response (pCR i.e.ypT0/ypN0) at surgery.
(3) RESULTS
Cell survival after treatment in the breast cancer spheroid model proved to be a sensitive and specific predictor for pCR in individual breast cancer patients. A mean cell survival of 21.8% was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8% in 56 patients without pCR (P = .001). A receiver operator characteristic analysis determined an area under the ROC curve of 0.86 (95% CI: 0.77 to 0.96) for cell survival compared to classic factors i.e. negative hormone receptor and positive Her2/neu status, and age ≤ 50 years at primary diagnosis (AUC = 0.80, 95% CI: 0.70 to 0.90). A cutoff of 35% cell survival was proposed, which grouped patients according to likelihood for pCR. Out of the 32 patients with values below this threshold, 21 patients (65.6%) and one patient (2.2%) with a cell survival greater than 35% achieved pCR respectively; (sensitivity 95.5% (95% CI: 0.86 to 1.00); specificity 80.4% (95% CI: 0.70 to 0.91)).The specificity was improved to 81% (95% CI: 58 to 95%) if the patient was treated per-protocol.
A positive correlation was also found between cell survival in vitro and residual tumor size (P = .021), indicating the possibility of the model to predict degree of response.
(4) CONCLUSION
The breast cancer spheroid model is a valuable predictor for treatment outcome in patients undergoing neoadjuvant chemotherapy for primary breast cancer. Preclinical selection of the most efficient drugs is a prerequisite to improve pCR.
Citation Format: Kathrin ML Halfter, Nina Ditsch, Hans-Christian Kolberg, Holger Fischer, Tanja Hauzenberger, Franz Edler von Koch, Ingo Bauerfeind, Gunter von Minckwitz, Ilona Funke, Alexander Crispin, Barbara Mayer. Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy – The SpheroNEO study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-13.
Abstract P3-06-20: A seven-gene signature can predict distant recurrence in patients with triple-negative breast cancers (TNBCs) who receive adjuvant chemotherapy following curative surgery of the primary breast cancer
Authors: Park Yeon Hee , Jung Hae Hyun , Do In-Gu , Cho Eun Yoon , Sohn Insuk , Jung Sin-Ho , Kil Won Ho , Kim Seok Won , Lee Jeong Eon , Nam Seok Jin , Ahn Jin Seok , Im Young-Hyuck 
Published: May 2015

Abstract
BACKGROUND: Women with triple-negative breast cancers (TNBCs) represent a significant treatment challenge as they have a relatively poor prognosis and no effective targeted therapy exists. Although TNBCs are often discussed as a single disease entity of breast cancers, in fact they are very heterogeneous. The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate TNBCs among patients, who received adjuvant chemotherapy after curative surgery, into those with high or low risk for distant recurrence.
METHODS: We tested whether the results of a NanoString expression assay that targeted 245 prospectively selected genes and used mRNA extracted from paraffin wax-embedded tumor tissues would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high).
RESULTS: NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63, and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis in this patients’ cohort and were validated with cross-validation. The proportions of patients categorized as having low or high risk were 75% and 25%, respectively. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low- and high-risk groups according to gene expression signature were 62% (95% CI, 48.6–78.9%) and 85% (95% confidence interval, CI, 79.2–90.7%), respectively. When adjusting for tumor–node–metastasis (TNM) stage, the distant recurrence-free survival (DRFS)s in the low-risk groups were significantly longer than that in the high-risk group (p&lt;.001) in each of TNM stages I plus II, and III. In a multivariate Cox regression model, the gene expression signature provided significant predictive power jointly with the TNM staging system.
CONCLUSION: A seven-gene signature could be used as a prognostic model to predict DRFS in patients with TNBC who received curative surgery followed by adjuvant chemotherapy.
Citation Format: Yeon Hee Park, Hae Hyun Jung, In-Gu Do, Eun Yoon Cho, Insuk Sohn, Sin-Ho Jung, Won Ho Kil, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn, Young-Hyuck Im. A seven-gene signature can predict distant recurrence in patients with triple-negative breast cancers (TNBCs) who receive adjuvant chemotherapy following curative surgery of the primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-20.
Abstract P3-06-27: BRCAness is important to identify TNBC subtype resistant to taxanes
Authors: Ishikawa Takashi , Narui Kazutaka , Shimada Kazuhiro , Kida Kumiko , Oba Mari S , Tanabe Mikiko , Ichikawa Yasushi , Sugae Sadatoshi , Endo Itaru 
Published: May 2015

Abstract
BACKGROUND: Triple negative breast cancer (TNBC) is heterogeneous and consists of tumors associated with basal like, BRCA related and cancer stem cell (CSC) phenotypes. Although anti-cancer agents are substantial for treating TNBC, existing ones do not work in some subpopulation in TNBC at all. However, it has not been reported that subdivision of TNBC is useful for choosing ant-cancer agents.
AIM: To examine whether subdividing TNBC is beneficial for tailored chemotherapy and to identify predictive factors for existing anti-cancer agents in TNBC.
METHODS: Sixty-six TNBC cases from a randomized phase II trial comparing TCx6 (TC6) with FEC followed by docetaxel (FEC-D) as neoadjuvant chemotherapy for hormone receptor-negative breast cancer (Kanagawa Breast Oncology Group 1101 Study). TNBC was subdivided by 1) IHC of CK 5/6 and EGFR into basal- and non-basal subtypes, and 2) MLPA of BRCA1 into BRCA1 and non-BRCA1 subtypes. The pCR rates were examined according to each regimen and subtype. 3) The association of grade 3 pCR was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (topoIIα) by IHC and TOP2A by FISH for each regimen.
RESULTS: 1) In basal subtype, the pCR rate was significantly higher for FEC-D (42.9%) compared with TC6 (13.6%) (p=0.033), but it was equivalent in non-basal subtype (FEC-D vs TC: 25.0% vs 36.4%, p=0.554). 2) In BRCA1 subtype, it was more significant (FEC-D vs TC: 53.8 % vs 13.3%, p=0.022). 3) An association between pCR and low ALDH1 expression was found in both FEC-D and TC6 (OR: 3.75 and 2.73). High topo IIα protein expression was associated with pCR in FEC-D (OR: 3.5).
DISCUSSION: TC6 was less effective than FEC-D in basal subtype and BRCA1 subtype, showing that taxanes cannot exert their anticancer role in tumors with BRCA1 dysfunction. Although basal subtype may contain more BRCA1-defective tumors than non-basal subtype, MLPA of BRCA1 was better to identify subtype resistant to taxanes than CK5/6 and EGFR. ALDH1 predicted treatment efficacy, and could therefore represent a marker of resistance to conventional chemotherapy.
Citation Format: Takashi Ishikawa, Kazutaka Narui, Kazuhiro Shimada, Kumiko Kida, Mari S Oba, Mikiko Tanabe, Yasushi Ichikawa, Sadatoshi Sugae, Itaru Endo. BRCAness is important to identify TNBC subtype resistant to taxanes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-27.
Abstract P3-06-31: Patient-derived xenografts accurately predict patient response in breast cancer patients
Authors: Stow Lisa , Katz Amanda , Irie Hanna , Port Elisa , Stebbing Justin , Ciznadija Daniel , Davies Angela , Paz Keren 
Published: May 2015

Abstract
PURPOSE/OBJECTIVES: A growing body of evidence demonstrates that patient-derived xenografts (PDXs) represent living tumor models that accurately reflect the biology of the primary patient tumor. More importantly, we have previously shown that PDX models show responses to therapeutic agents that are concordant with patient clinical response and can be used to direct personalized cancer treatments (Stebbing, 2014). Here we report the ability of PDX models to predict for patient response to drug treatment in a cohort of breast cancer patients.
MATERIALS/METHODS: Tumors were resected from patients with either primary or metastatic breast cancer and implanted into immunodeficient mice to establish PDX models. Successfully engrafted PDX models were expanded and randomized for drug sensitivity testing. Tumor growth inhibition and tumor regression were captured and results were correlated with a patient’s clinical response. In some cases, PDX results were used to personalize cancer treatment and some patients used PDX-directed treatments over multiple lines of therapy.
RESULTS: A total of 42 tumors from 40 patients were implanted resulting in 21 successfully engrafted PDX models (50% engraftment rate). Notably, engraftment rates were much higher for patients with triple negative breast cancer (TNBC) and resulted in 7 successful PDX models from 8 TNBC patients (87.5% engraftment rate). Drug sensitivity testing was offered to patients with established PDX models. Drugs and drug combinations tested included standard and nonstandard chemotherapy as well as biologics. At that time of this publication, 4 patients (3 TNBC and 1 HER2+) with completed drug sensitivity tests also had clinical data available resulting in 7 clinical correlations; 4 retrospective and 3 prospective. In all 7 cases, the PDX model accurately predicted patient clinical response demonstrating an accuracy of 100%. Five of the drug tests predicted drug sensitivity and 2 tests predicted resistance, indicating the potential of the PDX platform to predict for both sensitivity and resistance to therapy. The 3 prospective correlations resulted in concordant clinical benefit in 2 patients for duration greater than 6 months each.
CONCLUSIONS: These data support the use of the personalized PDX model as a platform for therapeutic decision making that can guide treatment for patients with breast cancer. A prospective clinical trial in TNBC is currently underway.
Citation Format: Lisa Stow, Amanda Katz, Hanna Irie, Elisa Port, Justin Stebbing, Daniel Ciznadija, Angela Davies, Keren Paz. Patient-derived xenografts accurately predict patient response in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-31.
Abstract P3-07-06: Survival benefit increases after breast conserving therapy compared to mastectomy when axillary node status is positive in early stage breast cancer: A registry based follow-up study of Norwegian women with screening and interval detected breast cancer pr
Authors: Hartmann-Johnsen Olaf Johan , Schlichting Ellen , Kaaresen Rolf , Nygaard Jan Franz 
Published: May 2015

Abstract
BACKGROUND: Recent register studies on early stage breast cancer have shown better survival when women underwent breast-conserving treatment (BCT) compared to mastectomy (MTX). It is unclear if this is due to selection effects or to a systemic benefit of BCT compared to MTX. If there is a systemic benefit this could theoretically be more prominent in some subgroups of breast cancer. The aim of this study is to evaluate if there are any subgroups with early stage breast cancer that benefits more of BCT compared to MTX.
METHOD: A cohort of 6.629 women aged 50-69 with primary operable breast cancer detected in the screening programme (on screening or between screening, interval cancer) were selected from January 1998 until December 2009 and followed up until end of 2010. Life tables for overall survival (OS) and breast cancer specific survival (BCSS) were calculated in surgery groups and stages. Corresponding Kaplan-Meier plots were stratified in T1N1M0 and Ductal Carcinoma. OS and BCSS were compared using Cox proportional hazard for estimating hazard ratio between BCT and MTX in crude and adjusted analysis.
RESULTS: 5-years BCSS in T1N0M0 was 99% for both surgical cohorts (BCT and MTX). 5-years BCSS in T1N1M0 was 98% for women undergoing BCT and 91% for women undergoing MTX. Respectively, 10-years BCSS in T1N1M0 was 96% for women undergoing BCT and 83% for women undergoing MTX.
In adjusted analysis, HR for breast cancer death for women with stage T1N1M0 undergoing MTX compared to BCT was 3.12 (95% CI: 1.71-5.72). Respectively, 3.67 (95% CI: 1.20-11.22) stratified on grade III and 4.89 (67 (95% CI: 1.25-19.01) stratified on hormone receptor negative disease.
CONCLUSION: The benefit of BCT compared to MTX seems to increase with increasing severity of the breast cancer disease, positive nodal status (N1), grade III and hormone receptor negative disease. These finding indicate a systemic benefit of BCT compared to MTX.
Citation Format: Olaf Johan Hartmann-Johnsen, Ellen Schlichting, Rolf Kaaresen, Jan Franz Nygaard. Survival benefit increases after breast conserving therapy compared to mastectomy when axillary node status is positive in early stage breast cancer: A registry based follow-up study of Norwegian women with screening and interval detected breast cancer pr [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-06.
Abstract P3-09-01: A multicenter randomized study comparing the dose dense G-CSF-supported sequential administration of FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive breast
Authors: Mavroudis Dimitrios , Malamos Nikolaos , Papakotoulas Pavlos , Kakolyris Stylianos , Boukovinas Ioannis , Athanasiadis Elias , Kentepozidis Nikolaos , Ziras Nikolaos , Kalbakis Kostas , Christophyllakis Charalambos , Georgoulias Vassilis 
Published: May 2015

Abstract
Background: The dose dense sequential administration of anthracycline and taxane is very effective as adjuvant therapy in node-positive early breast cancer. The non-anthracycline regimen docetaxel plus cyclophosphamide (TC regimen) was better than four cycles of doxorubicin/cyclophosphamide as adjuvant therapy. This study compared the dose dense sequential regimen versus the TC regimen as adjuvant therapy.
Methods: Women with axillary node-positive, HER2-negative early breast cancer were randomized following surgery to receive either dose dense G-CSF-supported FEC (5FU 500mg/m2, epirubicin 75mg/m2, cyclophosphamide 500mg/m2 every 14 days for 4 cycles) followed by Docetaxel (75mg/m2 every 14 days for 4 cycles) (arm A) or 6 cycles of Docetaxel 75mg/m2 plus Cyclophospamide 600mg/m2 every 3 weeks (arm B). The primary endpoint of the study was the 3-year disease-free survival (DFS).
Results: Six hundred fifty patients were randomized; 326 on arm A and 324 on arm B. Of them 109 (33%) and 90 (28%) were premenopausal, 196 (60%) and 218 (67%) had 1-3 positive nodes, 284 (87%) and 288 (89%) were hormone receptor positive in arm A and B, respectively. Chemotherapy was completed in 97% and 93% of patients in arm A and B, respectively. After a median follow up of 46 and 47 months, there were 37 (11.3%) and 33 (10.1%) disease relapses and the median DFS has not yet been reached (p=0.5) while the 3-year DFS rate was 89.5% and 91.1% for arm A and B, respectively. Neutropenia grade III-IV was more common in arm B and anemia, nausea, vomiting and fatigue grade II-III in arm A. No toxic deaths occurred.
Conclusions: The 3-year DFS rate was similar between the dose dense sequential FEC/docetaxel combination and the TC regimen in women with node-positive HER2-negative early breast cancer.
Citation Format: Dimitrios Mavroudis, Nikolaos Malamos, Pavlos Papakotoulas, Stylianos Kakolyris, Ioannis Boukovinas, Elias Athanasiadis, Nikolaos Kentepozidis, Nikolaos Ziras, Kostas Kalbakis, Charalambos Christophyllakis, Vassilis Georgoulias. A multicenter randomized study comparing the dose dense G-CSF-supported sequential administration of FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive breast [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-01.
Abstract P3-10-07: Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients
Authors: Iwasa Tsutomu , Tsurutani Junji , Nishida Satomi , Komoike Yoshifumi , Nakagawa Kazuhiko 
Published: May 2015

Abstract
Introduction: Eribulin is a non-taxane microtubule dynamics inhibitor that has been proved to prolong overall survival in patients with advanced and recurrent breast cancer compared to treatment of physician’s choice. S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur as the effector drug with two modulators, gimeracil, and oteracil potassium, and has shown promising antitumor activity as a single agent for the treatment of advanced breast cancer. In the basis of these results, we aimed to assess the efficacy of the combination of these two drugs in patients with advanced and recurrent breast cancer. In this trial, we determined maximum tolerated dose (MTD) and phase II recommended dose of Eribulin and S-1 combination therapy.
Methods: A traditional 3+3 dose escalation design was implemented. 12 patients pre-treated with anthracycline and taxane were enrolled. As an initiation level, patients received s-1 50 mg/m2 from day1 to day14, and Eribulin 1.1mg/m2 on day1, and day8. In level 2, Eribulin dose was increased to 1.4mg/m2. In level 3, S-1 dose was increased to 80 mg/m2.
Results: In level 1 or 2, no dose limiting toxicity (DLT) was observed. In level 3, grade 3 hypokalemia occurred in 1 case. The level 3 dose level was determined as phase II recommended dose. Neutropenia was observed in all cases, 3 of which was grade 3 febrile neutropenia. However, other non-hematological toxicity was mild, and the toxicity of the both drugs
Safety (N=12)Adverse EventGrade 3/4Leukopenia3 (25%)Neutropenia10 (83%)Febrile Neutropenia3 (25%)Hypokalemia1 (8%)
was not enhanced by the combination. Partial response
Efficacy (N=12)CR0 (0%)PR5 (41%)SD≥24 weeks2 (17%)SD&lt;24 weeks3 (25%)PD2 (17%)Clinical Benefit7 (58%)Disease Control Rate10 (83%)
is confirmed in 5/11 patients with measurable lesions.
Conclusion: We have shown that treatment with Eribulin and S-1 is active and well tolerated in patients with advanced and recurrent breast cancer, suggesting that this combination therapy may have potential as a new treatment option. A phase II study is being conducted to evaluate the efficacy and safety.
Citation Format: Tsutomu Iwasa, Junji Tsurutani, Satomi Nishida, Yoshifumi Komoike, Kazuhiko Nakagawa. Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-07.