bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-13-12: [bold]The adjuvant PANTHER study - A randomized comparison between dose-dense and tailored epirubicin (E), cyclophosphamide (C) and docetaxel (D) vs. standard dose 5-fluorouracil (F), epirubicin (E), cyclophosphamide (C) and docetaxel – First report on q
Authors: Brandberg Yvonne , Bengtsson Nils-Olof , Greil Richard , Möbus Volker , Malmström Per , Johansson Hemming , Andersson Harald , Hellström Mats , Gnant Michael , von Minckwitz Gunter , Bergh Jonas ,   the Swedish Breast Cancer Group,   the Austrian Breast-Colorectal Study Group and German Breast Cancer Group
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-12.
Abstract P1-14-21: High antitumoral activity of neoadjuvant chemotherapy (NCT) with weekly paclitaxel + capecitabine and trastuzumab in patients with locally advanced HER2+ breast cancer (HER2+ LABC): Preliminary results.
Authors: Augereau P , Raro P , Verriele V , Delva R , Abadie-Lacourtoisie S , Ceban T , Paillocher N , Valo I , Maillart P , Soulie P
Published: August 2014

Background: The addition of targeted agent (trastuzumab and/or pertuzumab and/or lapatinib) to NCT has dramatically improved pathological complete response rate (pCR) against HER2+ LABC. Early introduction of trastuzumab may be determinant as suggested by adjuvant trials while anthracycline free chemotherapy limits the risk of cardiotoxicity.

Treatment and methods: From 01/2006 to 08/2011, 55 patients with HER2+ LABC (defined by 3+ or SISH+, confirmed by an expert pathologist) were considered for this regimen: paclitaxel 80mg/m2/wk D1/8/15 q4wk; capecitabine (fixed dose) 1500 mg bid, 5d/wk, 3 wk/4; trastuzumab (T) 4 mg/kg loading dose (D1 cycle1), 2mg/kg D1/8 and 4mg/kg D15 q4wk, for a total of 6 cycles (1 cycle = 4 weeks). Additional trastuzumab (6mg/kg) was given q3wk for 9 cycles. Mastectomy was considered for multifocal CIC, extended DCIS, initial inflammatory tumor and post operative radiotherapy was given if indicated.

Patient characteristics: Median age: 58 years [28–84]; tumor stage II/III: 53%/47%; T1-2: 44%, T3: 36%, T4ac/d: 4%/16%; N0: 42%; median tumor clinical size: 4,6 cm [1–10]; grade III: 51%, HR−/HR+: 51%/49%. All patients were CT naïve.

Results: Median follow-up was 27 months [9–74]. Clinical activity: major response (CR+PR) was observed in all patients (84% cCR). Pathological activity: 63,5% of patients achieved a tumor and nodal pCR (Sataloff TANA or NB, without residual invasive tumor cells), 22% had residual DCIS. According to hormonal receptor status (HR), pCR was 89% in HR−, 37% in HR+. Surgery was conservative in 37 patients (67%). 2 patients had locoregional recurrence (T4dN3, T3N1, both pCR and HR−).

Toxicity (NCI-CTC scale):. Only 6 patients stopped either paclitaxel or capecitabine before the 6th cycle (1 at Cycle 3, 2 at cycle 5, and 3 at cycle 6). Main toxicities were: mucositis grade (gr) ½: 34%; diarrhea gr½: 27%; hand foot syndrome gr ½: 40%, gr 3: 9%; peripheral neuropathy gr ½: 39%, gr 3: 6%; asthenia gr ½: 47%, onychopathy gr½: 33%; gr 3: 6%; neutropenia gr 3: 9%, no febrile neutropenia. Two patients have a grade 2 reversible cardiotoxicity (LVEF < 50 %)

Conclusion:. This NCT provided high pCR, specially in the HR- subgroup with a very favourable toxicity profile and merits further exploration.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-21.
Abstract P2-01-14: circulating tumor cells in breast cancer exhibit dynamic changes in epithelial and mesenchymal cell composition
Authors: Yu M , Bardia A , Wittner BS , Stott SL , Smas ME , Ting DT , Isakoff SJ , Ciciliano JC , Wells MN , Shah AM , Concannon KF , Sequist LV , Brachtel E , Sgroi D , Baselga J , Ramaswamy S , Toner M , Haber DA , Maheswaran S
Published: August 2014

Epithelial to mesenchymal transition (EMT) has been postulated to contribute to the migration and dissemination of cancer cells, but supporting histopathological evidence is limited. We used a microfluidic device to isolate circulating tumor cells (CTCs), combined with multiplex fluorescent RNA-in-situ hybridization (ISH) and RNA sequencing, to quantify and characterize EMT in breast cancer cells within the bloodstream. Whereas only rare (0.1–10%) cells in the primary tumor expressed both mesenchymal and epithelial markers, such biphenotypic as well as purely mesenchymal cells were enriched among CTCs, across all histological subtypes of breast cancer. Analysis of the therapy response in 8 patients suggest an association of mesenchymal CTCs with disease progression. In an index patient followed longitudinally, fluctuation in epithelial and mesenchymal states was observed as a function of initial response and subsequent resistance to therapy. Mesenchymal markers were predominant in clusters of tumor cells, many of which had adherent platelets. Finally, RNA sequencing of mesenchymal CTC clusters identified TGF-B and other EMT-related signatures, which were absent from more epithelial CTCs. FOXC1, a known regulator of EMT, was abundantly expressed in mesenchymal CTCs and was detectable within localized regions of the primary breast tumor. Together, these data support a role for EMT in the blood-borne dissemination of breast cancer and point to the dynamic nature of this cell fate change.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-14.
Abstract P2-02-03: The Collagen Receptor Endo180: A Metastatic Plasma Marker In Breast Cancer Modulated By Bisphosphonate Treatment
Authors: Sturge J , Caley MP , Purshouse K , Fonseca A-V , Rodriguez-Teja M , Kogianni G , Waxman J , Palmieri C
Published: August 2014

Purpose: To establish whether the collagen remodelling receptor, Endo180, should be given consideration as a useful plasma marker in metastatic breast cancer.

Patients and Methods: Analysis of MCF-7 and MDA-MB-231 cell conditioned medium validated the anti-human (39.10) monoclonal antibody as suitable for the detection of soluble Endo180 in plasma. Eighty-seven breast cancer patients with early primary, locally advanced and metastatic disease were included in the study. Correlations between Endo180, CA 15–3 antigen (MUC1; mucin 1) and bisphosphonate treatment were investigated.

Results: Endo180 was elevated in metastatic compared to early breast cancer (P <.0001) and was able to differentiate locoregional disease and visceral and/or osseous metastasis (P = .0005). In combination CA 15–3 antigen (cut-off: 28 U/mL) and Endo180 (relative plasma level cut-off range: 0.95–1.65) had sensitivity of 94–97% and specificity of 52–68%. Endo180 levels were significantly higher in patients who were treatment naive (2.17 ± 0.82, N = 13) compared to those previously (1.82 ± 0.33, N = 5) or currently (1.37 ± 0.74, N = 24) receiving bisphosphonates (P = .011). In the bisphosphonate naive setting (N = 57) the combination of Endo180 (relative plasma level cut-off range: 0.95–1.65) and CA 15–3 antigen (cut-off: 28 U/mL) had a sensitivity of 87–92% and specificity of 72–79%.

Conclusion: Endo180 is a plasma marker with high sensitivity in metastatic breast cancer that can be modulated by bisphosphonate treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-02-03.
Abstract P2-04-01: Development of mouse breast cancer models based on induced cancer stem cells (iCSC).
Authors: Takamoto Y , Onishi N , Kai K , Saya H
Published: August 2014

Breast cancer is one of the leading causes of death in women worldwide. To develop novel therapeutic approaches for the refractory cases, the mouse models which recapitulate the tumor tissues biologically and pathologically similar to human breast cancer are required. Although xenograft models of established cell lines in immune-deficient mice are frequently used for preclinical experiments, such xenograft models are not sufficient because the heterogenous structure based on the microenvironment and the intrinsic characteristics of cancer cells is not correctly formed.

In this study, we have established induced cancer stem cells (iCSC) from normal mouse mammary stem/progenitor cells through minimal required genetic manipulations and generated mouse breast cancer models by inoculating the iCSCs in the mammary fat pads. Initially, we established iCSC by introducing the H-RasV12 into Ink4a/Arf-knockout mammary stem/progenitor cells and this iCSC formed tumor similar to human triple negative breast cancer in mouse. This finding suggested that two genetic events, an activation of oncogenic signal and a tumor suppressor inactivation, are required for generating the breast cancer iCSC.

Anaplastic Lymphoma Kinase (ALK) gene, which encodes a receptor tyrosine kinase, was reported to be amplified and/or overexpressed up to 86% of patients in inflammatory breast cancer, and pleiotrophin (PTN), which is a physiological ligand for ALK, was also shown to be highly expressed in about 60% of human breast cancers. Therefore, we hypothesized that ALK pathway is involved in tumorigenesis of breast cancers and, then, attempted to generate iCSC by using ALK gene. Interestingly, we found that one of the naturally occurring mutations of ALK is sufficient for generating iCSC and tumor formation in vivo without any prior tumor suppressor inactivation. The ALK-induced iCSCs developed highly aggressive breast cancers in mice. Furthermore, the tumor formation was significantly suppressed when the ALK-induced iCSCs were generated by using mammary stem/progenitor cells derived from mouse deficient in CD44 which is a CSC marker. We have recently revealed a role of CD44, in particular that of a variant isoform (CD44v), in the protection of CSCs from high levels of oxidative stress derived from both tumor cells and their microenvironment (Cancer Cell 19: 387–400, 2011; Cancer Res 72: 1438–1448, 2012; Nat Commun 3: 883, 2012). We will discuss the underlying mechanism of ALK-induced tumorigenesis and a role of CD44 in the CSC functions.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-01.
Abstract P2-05-02: Clinical significance of microRNA regulator Lin28 expression in patient with early breast cancer
Authors: Park S , Shin YK , Song BJ , Chae BJ , Jung SS , Choi Y-L
Published: August 2014

Lin28 is an RNA-binding protein that is highly expressed in human embryonic stem (ES) cells. It can facillatate the reprogramming of human somatic cells to pluripotency with other stem cell marker proteins (Oct4, Nanog and Sox2). Lin28 regulates the processing of microRNAs including let-7 (Mirlet7) and translation of specific subset of cell cycle-related genes such as IGF-2, OCT4. Recently, it has been suggested that Lin28 expression may contribute to breast cancer metastasis in an animal model (Dangi-Garimellaet al., 2009).

To define clinical impact of Lin 28 in breast cancer, we investigated Lin28 expression in tumors from patients with early breast cancer who underwent curative resection of tumor.

To define prognostic impact of Lin 28 in breast cancer, we investigated Lin28 expression in patients with early breast cancer who underwent curative resection of tumor. In all, 950 slides from paraffin-embedded tissue were available for analysis by Lin28 expression by immunohistochemistry (IHC), and 78 cases (13.2%) were identified as Lin28-positive. Lin28 positivity was significantly associated with more advanced stage (P < .001), lymph node involvement (P< .001), absence of estrogen receptor expression (P = .002), negative progesterone receptor expression (P = .017), HER2 overexpression (P< .001), higher histologic grade (P = .008), and higher tumor grade (P = .012). The Lin28 positive patients with early breast cancer demonstrated substantially poorer relapse free survival (Lin28+ positive vs. Lin28−(P = 0.013) and trends toward poorer overall survival.

Taken together, a sub-population of breast cancer with Lin28 expression is significantly associated with aggressive tumor phenotype and poor clinical outcome.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-02.
Abstract P2-05-09: Identification and validation of a miRNA signature associated with breast cancer progression
Authors: Waters PS , Dwyer RM , Kerin MJ
Published: August 2014

Introduction: MiRNAs are aberrantly expressed in both the circulation and tissue of patients with breast tumours, however little is currently known about the relationship between circulating and tissue miRNAs. The aim of this study was to quantify circulating and tumour tissue miRNA expression in a murine model of breast cancer and identify novel circulating markers of disease progression.

Materials and Methods: Athymic nude mice (n = 20) received either a mammary fat pad (n = 8, MFP), or subcutaneous (n = 7, SC) injection of MDA-MB-231 cells. Controls received no tumour cells (n = 5). Tumour volume was monitored weekly and blood sampling performed at weeks 1, 3 and 6 following tumour induction (total n=60). Animals were sacrificed at week 6 and tumour tissue (n = 15), lungs (n = 20) and enlarged lymph nodes (n = 3) harvested. RNA were extracted from all samples (n = 98) and relative expression of miRNAs previously associated with tumour progression were quantified using RQ-RCR. A microRNA array was also preformed comparing animals with early (weeks 1, n=5) versus late (week 6, n=5) disease and results were analysed using RQ-PCR in all blood samples (n = 60). Reverse transcription for the relevant targets and endogenous controls was carried out and expression was quantified using RQ-PCR.

Results: MiR-10b expression was significantly higher in MFP compared to SC tumours (p < 0.05), with the highest levels in diseased lymph nodes (p < 0.05). MiR-10b was undetectable in the circulation. MiR-221 expression was significantly increased in tumour tissue (p < 0.001). MiR-195 and miR-497 were significantly decreased in tumour tissue (p < 0.05), and also in the circulation of animals 3 weeks following tumour induction (p < 0.05). At both tissue and circulating level, a significant correlation was observed between miR-497 and miR-195 (r = 0.61, p < 0.001; r = 0.41, p < 0.01 respectively). Microarray analysis revealed the level of 47 miRs to be significantly changed between week 1 and week 6 as disease progressed in a murine model, 10 of which (miR A-J) were significantly altered and internally validated within the murine model.

Conclusions: This study highlights the importance of miRNAs in breast cancer, with each displaying distinct roles in circulation and tissue. Novel circulating miRNAs which have never previously been associated with breast cancer have been identified, with quantification of circulating levels in breast cancer patients currently ongoing.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-09.
Abstract P2-05-17: Correlation between cyclin D1, estrogen and progesterone receptors in invasive breast cancer after short-term treatment with tamoxifen or anastrozole
Authors: Millen EC , Mattar A , Logullo AF , Nonogaki S , Soares FA , Gebrim LH
Published: August 2014

INTRODUCTION: Hormone therapy is associated with reduced breast cancer mortality. The use of biomarkers that are predictive of early cellular responses has been explored as a predictor of hormone resistance. Estrogen and progesterone receptor positivity and cyclin D1 have been associated with resistance to treatment with tamoxifen.

OBJECTIVES: The aim of this study was to investigate the variations in the levels of cyclin D1 and the estrogen and progesterone receptors (ER and PR, respectively) in postmenopausal patients with ER− or PR-positive breast cancer after short-term treatment (26 days) with tamoxifen, anastrozole or a placebo.

METHODS: This was a prospective, randomized double-blind study conducted in 71 patients with infiltrating ductal carcinoma (stages II and III) receiving care at either Pérola Byington Hospital or São Paulo Hospital (São Paulo, Brazil). The patients were divided into three groups based on their treatment during the preoperative period (26 days): P (placebo, N = 26), T (tamoxifen, 20 mg/day, N = 22) and A (anastrozole, 1 mg/day, N = 23). The biopsies were performed at diagnosis and after mastectomy (26th day), and the tumors were isolated by tissue microarray. Immunohistochemistry was performed using anti-cyclin D1 (Novocastra DCS-6), anti-ER (Dako-M7047) and anti-PR (Dako-M3569) antibodies. The semiquantitative analyses were performed using Allred criteria, and the statistical analyses were performed with the ANOVA parametric test (p ≤ 0.05).

RESULTS: A reduction in the mean PR level from 4.22 (pre-treatment) to 1.94 (post-treatment) was observed only in patients treated with anastrozole (p = 0.01). A positive linear correlation between cyclin D1 and PR levels was observed in group A (p = 0.0001), whereas group T exhibited a negative correlation (p = 0.0001). No correlation was observed in group P (p = 0.35).

CONCLUSION: PR and cyclin D1 are likely predictive of an early response to aromatase inhibitors in breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-17.
Abstract P2-05-18: Deregulation of the Abl interactor 1 signaling as a potential biomarker for metastatic breast cancer.
Authors: Tang Hongxing , Lockman Paul , Tao Yunxia , Dai Zonghan
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-18.
Abstract P2-06-02: Genomic evolution from primary breast cancers to distant metastases
Authors: Hoefnagel LDC , Moelans CB , van der Groep P , van der Wall E , van Diest PJ
Published: August 2014

Purpose: Genomic evolution is an accepted concept during cancer development and progression. However, little is known about the changes that occur during the metastatic process despite the fact that breast cancer metastases are the leading cause of death in breast cancer patients. The purpose of this study was therefore to investigate whether distant breast cancer metastases show progression in copy number changes of onco- and tumor suppressor genes compared to their primary tumor.

Material and methods: Multiplex ligation-dependent probe amplification (MLPA) was used to compare copy number of 21 established oncogenes and tumor suppressor genes between primary breast cancer samples and corresponding distant metastases in 55 patients. Genes studied were ESR1, EGFR, FGFR1, ADAM 9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.

Results: Overall, there was no significant difference in mean copy number between primary tumors (1.26 +/− 0.6) and metastases (1.27 +/− 0.64) (p = 0.826), but on the individual gene level, mean copy number for PRDM14 (p = 0,023), MED1 (p = 0.001) and CCNE1 (p = 0.039) were significantly higher while TRAF4 (p = 0.038) copy number was significantly lower in the metastases. Using dichotomized MLPA data, MTDH amplifications were significantly more frequent in the primary cancers compared to the metastases (27.3% vs.14.6%, p = 0.039), while significantly more CDH1 losses were found in the metastases compared to the primary tumor (23.6% vs. 9.1%, p = 0.039).

Conclusion: Distant breast cancer metastases show genomic evolution from the primary cancer as reflected by copy number changes in several established onco- and tumor suppressor genes.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-02.
Abstract P2-10-12: How well predict the 2011 St Gallen early breast cancer surrogate phenotypes metastatic survival?
Authors: Vanderstichele A , Brouckaert O , Tuyls S , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Peeters S , Moerman P , Floris G , Paridaens R , Wildiers H , Vergote I , Christiaens M-R , Van Calster B , Neven P
Published: August 2014

BACKGROUND: The five prognostic surrogate phenotypes, defined by the 2011 St Gallen consensus, predict metastatic relapse following early breast cancer treatment (Brouckaert et al Ann Oncol 2012). It is unknown to what extent these surrogate phenotypes defined on the primary tumor predict metastatic survival (MS) in a cohort of consecutive women with metachronous metastases.

PATIENTS & METHODS: All 4318 patients with primary operable breast cancer, diagnosed between 01–01-2000 and 31–12-2009 and treated in our center were prospectively entered in our institutional database. We included 345 patients with a (distant) metastatic relapse during their follow-up. We observed metastatic survival as the time between the diagnosis of the relapse and death. Tumor subtype was defined according to the 2011 St Gallen recommendations in 5 groups: luminal A (ER+/HER2−, grade 1–2), luminal B1 (ER+/HER2−, grade 3), luminal B2 or luminal-HER2 (ER+/HER2+), HER2-like (ER−/HER2−) and triple-negative. We focused on the value of the primary tumor subtype as a major prognostic determinant, but also assessed age at diagnosis, tumor size, lymph node involvement, tumor subtype, PR-status, primary detection (screening vs. palpation), histology, adjuvant therapy, distant-metastasis free interval (DMFI), first-line metastatic hormonal therapy, recurrence sites (isolate or multiple) and metastasis detection (clinical vs. biochemical).

RESULTS: In our cohort, we recorded a median metastatic survival (MS) of 22.3 months (95% CI: 19.7–25.6) and a 5-year survival probability of 15%. Significant differences in median MS were noted when considering the primary tumor subtype (cf. table).

We observed an independent prognostic effect for multiple recurrence sites (HR = 1.78, 95% CI 1.37–2.32), first-line metastatic hormonal therapy (HR = 0.30, 95% CI 0.18–0.49), DMFI (HR = 0.92 CI 0.85–0.98) and, finally, primary tumor subtype.

CONCLUSION: Our results showed that primary tumor subtype, DMFI, solitary recurrence and first-line metastatic hormonal therapy act as independent prognostic factors in metastatic breast cancer.

In order to overcome the biological complexity of metastatic breast cancer, we must appreciate the primary tumor subtype in our therapeutic approach.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-12.
Abstract P2-10-14: Triple Negative Breast Cancer: prognosis of triple-negative breast cancers and non-triple-negative breast cancers in a large registry of certified breast units
Authors: Kern P , Rezai M
Published: August 2014

Background: Prognosis of Triple-Negative Breast Cancer (TNBC) and non-TNBC has been evaluated predominantly in smaller subset of patients, and pooled analyses include various subsets of institutional standards.

The West German Breast Center includes more than 200 certified breast units covering approx. 65 % of all breast cancer cases in the country.

Material and Methods: We included all primary breast cancer cases of the last 3 years whenever patients received any kind of neoadjuvant or adjuvant chemotherapy in all certified breast units affiliated to the West German Breast Center.

Data was submitted in a computer-based registry, where standardized data is prospectively collected. Data monitoring and benchmarking is held 6-monthly which guarantees a high standard of performance.

Results: 34 675 non-TNBC patients achieved a DFS of 92,4 % at 2 years and 81,2 % at 3 years whereas out of 3728 TNBC-patients only 79 % were disease-free at 2 years and 57,4 % at 3 years.

With regards to overall survival 97,3 % of non-TNBC patients were alive at 2 years and 92,2 % at 3 years, whereas 89,3 % TNBC-patients were alive at 2 years and 82,9 % at 3 years.

Conclusion: In this large registry of certified breast units from the West German Breast Center we could underline the significant differences of prognosis as to DFS and OS between the non-TNBC and TNBC-subgroup of patients, displaying survival rates with modern 3rd generation chemotherapy, surgical treatment and radiotherapy in a controlled setting with prospectively collected data.

To is, to our best knowledge, one of the largest data sets ever exploring the differences in prognosis between TNBC and non-TNBC-patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-14.
Abstract P2-10-24: Independent validation of Recurrence Online using 1,638 breast cancer microarray samples
Authors: Györffy B , Weltz B , Benke Z , Timar J , Sztupinszki Z , Schaefer R
Published: August 2014

Background: RecurrenceOnline.com uses Affymetrix microarrays to compute the recurrence score and to measure estrogen receptor and HER2-receptor status for breast cancer patients. Our aim was to assess the efficacy of measuring HER2 status as well as the accuracy of survival prediction using an independent set of breast cancer gene expression profiles.

Methods: In GEO, we mined new datasets published after the release of Recurrence Online containing detailed clinical characteristics of the profiled cancer patients. The raw microarray data were downloaded and each array was analyzed by running the algorithm available at www.recurrenceonline.com. Then, the subgroups were compared using Kaplan-Meier analysis. For HER2 status determination, the immunohistochemistry (IHC)-based HER2 results were correlated to the microarray results. The cut-off value for HER2 mRNA positivity was set to 4,800. The accuracy was assessed using chi-square tests.

Results: Altogether 1,638 new breast cancer samples were analyzed in 9 GEO datasets (these include GSE16446, GSE17907, GSE19615, GSE25066, GSE20711, GSE26971, GSE31448, GSE31519, and GSE20685). The average relapse-free survival among these patients was 4.51 years, 68% of patients were ER positive and 672 were lymph node positive. RecurrenceOnline was capable to classify all patients into good and bad prognosis groups with high accuracy in all patients (p = 2.04E−09), and with p = 1.6E−03 after excluding lymph node positive samples. HER2 IHC data were published for 1,177 patients, with 12% of the patients being positive. HER2 status was correctly assessed for 93% (p < 7E−20) of the patients.

Discussion. We verified the classification accuracy of RecurrenceOnline using independent datasets. Our results further support the feasibility of using genome-wide microarrays for patient classification.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-24.
Abstract P2-10-33: Mitotic Component of Grade Can Distinguish Breast Cancer Patients at Greatest Risk of Local Relapse
Authors: Done SJ , Miller NA , Wei Shi W , Pintilie M , McCready DR , Liu F-F , Fyles A
Published: August 2014

Background: With the recent recognition of many different molecular subtypes of breast cancer a desire to more specifically categorize tumors to allow tailoring of treatment to individual patients has developed. This has largely involved the development of molecular tests rather than the re-examination of current pathologic criteria. We wanted to evaluate standard pathologic features to determine their ability to predict for local recurrence.

Materials and Methods: Slides were retrieved for review from 280 of 769 women who had participated in a trial of tamoxifen with or without breast irradiation between December 1992 and June 2000 and for whom outcome data up to 18 years was available. All women were 50 years of age or older at the time of enrollment and had T1 or T2 node negative breast cancer. The cases for which slides were obtained were representative of the whole group. The slides were reviewed by two breast pathologists (SJD and NAM). Several features were evaluated; modified Nottingham histologic grade and its components- degree of tubule formation, nuclear pleomorphism and mitotic count. Mitotic component of grade was calibrated to the microscopic field size used. The presence of lymphatic/vascular space invasion was also scored. A statistical analysis was performed to relate these pathologic features to local recurrence at up to 18 years.

Results: The strongest predictor of local recurrence was the mitotic component of the Nottingham histologic grade with 5.7% for mitotic score 1/3 (n = 200), 19.6% for mitotic score 2/3 (n = 37) and 19.8% for mitotic score 3/3 (n = 43)(Gray's p-value = 0.0021). Overall grade was also able to predict for local recurrence with 2.6% for Grade 1 (n = 49), 10.6% for Grade 2 (n = 162) and 17.9% for Grade 3 (n = 71)(Gray's p-value=0.026). However, neither architecture (0% vs. 9.5% vs. 9.8%, Gray's p-value=0.74) nor degree of nuclear pleomorphism (0% vs. 7.9% vs. 11.5%, Gray's p-value=0.37), the other components of histologic grade, showed a statistically significant difference for recurrence. The presence or absence of endothelial lined space invasion was also found to be not statistically different (9.3% vs. 13%, Gray's p-value=0.55).

Conclusion: Within this cohort of tamoxifen treated T1 and T2 breast cancer patients 50 years of age or older, mitotic index could stratify women into groups with high and low risk of recurrence. If validated this may be a useful way of allocating patients to different treatment groups. Additional validation studies are planned on similar groups of patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-33.
Abstract P2-10-38: Prognostic factors uPA/PAI-1: measurement in core needle biopsies
Authors: Vetter M , Landstorfer B , Lantzsch T , Buchmann J , Große R , Ruschke K , Holzhausen H-J , Thomssen C , Kantelhardt E-J
Published: August 2014

Background: The urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 are validated as prognostic factors at the highest level of evidence within the node-negative group of breast cancer patients (Harris L et al., JCO 2007; 25:5287).

Usually, patients receive a core-needle biopsy before surgery. A prior feasibility study showed that the method of sampling (ex vivo from the surgical specimen using a small core needle or the larger excision specimen) doesn't influence the uPA and PAI-1 results (Thomssen et al., J Natl Cancer 2009; 101:1028). With the current study, we assessed how well uPA and PAI-1 values obtained from the core needle biopsy (in vivo) predict the expression level of these prognostic factors in the later surgical specimen.

Material and Methods: Fresh frozen material of 2–3 core needle biopsies (min 10 mg each) and the corresponding tumor material (min 50 mg) removed by subsequent surgery were collected from 110 patients in two hospitals. Only areas of the surgical specimen were selected for testing that had a sufficient distance to the needle biopsy defect. The uPA and PAI-1 concentrations were analysed using a commercially available ELISA test (FEMTELLE™; American Diagnostica, Inc., Stamford, CT). The predictive values (and sensitivity/specificity) of the core-needle biopsy data were calculated to forecast the uPA and PAI-1 values of the corresponding surgical specimen results.

Results: Sensitivity, specificity, the positive (ppv) and negative (npv) predictive values for uPA, PAI-1 and for the combination of uPA/PAI-1 are listed in table 1. Low concentrations of uPA in the core needle biopsies correlate with low concentrations in the surgical specimens across the entire study cohort as well as in the group with an intermediate (G2, N0) risk (npv = 0.91).

The clinical and pathological data of the cohort and the risk assessment will be presented.

Conclusion: Most important, low uPA/PAI-1 results in core-needle biopsies predict low results in the surgical specimen. In some cases, core-needle biopsies and surgical specimen show discordant data. These cases do not correlate with any clinical or pathological factors such as time between needling and surgery, grading, tumor size or hospital. We assume that these discordances are caused by pre-surgical manipulations, which change expression patterns in the remaining tissue as it is reported also from multi-gene tests.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-38.
Abstract P2-10-42: Gene expression profiling to predict the risk of locoregional recurrence in breast cancer
Authors: Drukker CA , Nijenhuis MV , Elias SG , Wesseling J , Russell NS , de Snoo F , van't Veer LJ , Beitsch PD , Rutgers EJT
Published: August 2014

Background The 70-gene signature (Mammaprint™) has been developed to predict the risk of distant metastases in breast cancer and select those patients who will have benefit in survival from adjuvant treatment. Aside from distant metastases, the development of locoregional recurrence is a significant predictor of survival. Given the strong association between locoregional recurrence and distant recurrence, we hypothesize that the 70-gene signature will be predictive of locoregional recurrence as well.

Methods We updated follow-up and radiotherapy details for all 1053 unique breast cancer patients treated at the NKI-AVL who previously participated in various 70-gene signature validation studies. Diagnosis was between 1984 and 2006. All patients were primarily treated surgically with either breast-conservation therapy or mastectomy. Adjuvant treatment consisted of radiotherapy, chemotherapy and/or endocrine therapy as indicated. Known risk factors for locoregional recurrence including age, tumor free resection margins, tumor size, grade, ER status, Her2 status, nodal irradiation and tumor bed boost were included in our analysis in addition to the 70-gene signature result.

Results Through 10 years of follow-up, 80 locoregional recurrences occurred. Patients with a 70-gene signature high risk result (n = 492) had a locoregional recurrence risk of 8.8% (95%CI: 6.3–11.3) at 5 years and 13.5 % (95%CI: 10.2–16.8) at 10 years, which was 2.6% (95%CI: 1.2–4.0) at 5 years and 5.7% (95%CI:3.5–7.9) at 10 years for patients with a low risk 70-gene signature (n = 561)(Logrank: p < 0.0001). Accordingly, patients with a high risk 70-gene signature had an approximately 3 times higher risk of locoregional recurrence than patients with a low risk 70-gene signature (univariable hazard ratio (HR) 2.89; 95%CI: 1.80–4.63). Adding the 70-gene signature to a Cox proportional hazard model containing age, size, grade, ER status, involvement of axillary lymph nodes, surgical treatment and adjuvant treatment (radiotherapy, chemotherapy and/or endocrine therapy), significantly improved the model (likelihood ratio: p = 0.007). In that model, the multivariable HR for high versus low 70-gene signature risk was 2.27 (95%CI: 1.24–4.15).

Conclusion The 70-gene signature is able to predict the risk of locoregional recurrence, independent of known risk factors. Using the 70-gene signature may help in selecting those patients who will benefit from extensive adjuvant treatment. Additionally, the 70-gene signature may also select a group of patients at a low risk of locoregional recurrence who may be cured with limited local treatment alone.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-42.
Abstract P2-11-11: Patient Reported Outcomes after Breast Cancer Surgery and Adjuvant Therapy from a German Breast Cancer Centre
Authors: Feiten S , Dünnebacke J , Heymanns J , Köppler H , Thomalla J , van Roye C , Wey D , Weide R
Published: August 2014

Objectives: Evaluation of the subjectively experienced physical, psychological, social and job-related consequences of breast cancer.

Methods: Standardized paper pencil interview of patients with the initial diagnosis of breast cancer who had their primary surgery between 01/2006 and 12/2010 at an accredited breast cancer centre followed by systemic adjuvant treatment. The data collection was conducted with the help of a self-developed scanner-readable questionnaire which had been evaluated in a pretest.

Results: 1260 patients were contacted, 871 completed questionnaires (return rate 72%) were analyzed. Median age of the patients (99.5% women) at the time of the interview was 65 years (30–91). 6% relapsed during the observation period. 91% were “satisfied” or “very satisfied” with the surgical result. 67% indicated a complete freedom of pain. 23% received lymphatic drainage at the time of the questioning (11/2011), 33% complained about limitations of arm and/or shoulder function. 76% received anti-hormonal therapy, 13% stopped the anti-hormonal medication prematurely. Patients received a mean of 1.3 different anti-hormonal therapies, 54% took Tamoxifen. Psychological distress, cognitive limitations and physical consequences were rated on a scale from 1 – “not at all” to 4 – “very much”. The highest average values were found for the items sleep disturbances (2.3) and exhaustion (2.3), the lowest for depression (1.7) and word-finding difficulties (1.8). After therapy only 39% described a complete recovery of their physical capacity, 62% regained their previous mental capacity. 44% were in employment before their disease. 67% returned to their workplace but only 65% of them with their previous number of hours. 15% indicated disadvantages in their workplace due to the breast cancer disease. For 75% their partnership did not change, 12% experienced a deterioration, 13% an improvement. Before the illness 9% consulted a psychiatrist/psychotherapist, after the illness 18%. Before the diagnosis of breast cancer 13% received antipsychotic drugs, after the disease 25%.

Conclusions: Breast cancer diagnosis and therapy leads to long lasting impairment of physical, psychological, social and job-related functioning in a significant number of patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-11.
Abstract P2-12-03: A pilot study evaluating the benefits and feasibility of an exercise program for breast cancer patients receiving adjuvant chemotherapy.
Authors: Petrella TM , Laredo S , Oh P , Marzolini S , Warner E , Dent R , Verma S , Eisen A , Pritchard K , Trudeau M , Zhang L , Bjarnason G
Published: August 2014

BACKGROUND: Breast cancer chemotherapy is frequently associated with a decline in general physical condition, exercise tolerance, muscle strength and quality of life (QOL). Evidence suggests that physical activity and exercise interventions during chemotherapy treatment may contribute to maintaining QOL, cardiorespiratory fitness and strength, however the results of studies conducted to date have not been consistent.

OBJECTIVES: This study aimed to determine the effect of a structured, tailored exercise program involving both aerobic and resistance training, on QOL, physical function, and body composition in breast cancer patients undergoing adjuvant chemotherapy.

METHODS: Women who were within 4–12 weeks of surgery for stage I-III breast cancer and undergoing adjuvant chemotherapy, were randomized to either a structured exercise program (6 months) or to usual oncology care. Functional assessment of cancer therapy-breast cancer (FACT-B), and Short Form Survey (SF-36), weight, waist circumference, waist hip ratio, percent body fat, peak oxygen, strength and arm volume were performed at baseline, and 3-month intervals through 12 months. One-way analysis of variance (ANOVA) was performed at baseline, 3, 6 and 12 months for all endpoints. The Wilcoxon Rank-sum Nonparametric test was applied for all Primary and Secondary endpoints with changing scores at each follow-up visit, p-value < 0.05 was considered as statistical significance.

RESULTS: Of the recruited 62 women, 51 completed all 12 months. One patient developed metastatic disease and 10 others withdrew (4 in the exercise arm and 6 in the standard arm). Median age was 48 (24–75) years. There was a general trend of improvement from baseline for most components of the FACT-B and SF-36 for the exercise group but only the FACT-B social wellbeing was statistically significant at 3 months with a p = 0.0164. Changes in other FACT-B and SF-36 scores were not significantly different between exercise and usual care groups. There were significant improvements at 6 months in weight (p = 0.0192), % body fat (p = 0.0337), max strength (p = 0.0029), and waist circumference (0.0359) and at 12 months in weight (p = 0.0293), % body fat (p = 0.0481), max strength (p = 0.0097) and endurance (p = 0.0037) in the exercise group compared to usual care.

CONCLUSIONS: This randomized prospective study suggests benefit of exercise during chemotherapy. This benefit continued 6 months beyond the completion of the exercise program with significant improvement in physical function, body composition, strength and endurance with no decline in quality of life. Regular moderate exercise may play an important role in improving function during adjuvant chemotherapy and should be further studied in a large randomized trial.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-03.
Abstract P2-12-09: A randomized controlled trial of support group intervention after breast cancer treatment: Results on sick leave, health care utilization and health economy.
Authors: Granstam Björneklett H , Rosenblad A , Lindemalm C , Ojutkangas M-L , Letocha H , Strang P , Bergkvist L
Published: August 2014

Background: More than 50% of breast cancer patients are diagnosed before the age of 65. Returning to work after treatment is, therefore, of interest for both the individual and society. The aim was, therefore, to study the effect of support group intervention on sick leave, health care utilization and health economy.

Material and Methods: Of 382 patients with newly diagnosed breast cancer, 191 + 191 patients were randomized to an intervention group or to a routine control group respectively.

The intervention group received support intervention on a residential basis for one week, followed by four days of follow-up two months later. The support intervention included informative-educational sections, relaxation training, mental visualization and non-verbal communication. Patients answered a questionnaire at baseline, 2, 6 and 12 months about sick leave and health care utilization.

Result There was a trend towards longer sick leave and more health care utilization in the intervention group. The difference in total costs was statistically significantly higher in the intervention group after 12 months (p = 0.0036)

Conclusion There was no economic benefit from intervention in its present form. In fact we saw a tendency towards longer sick leave and more health care utilization and we could show that the total cost in the intervention group was actually higher and that this difference was statistically significant after twelve months.

Key words: Support intervention, breast cancer, return to work, sick leave, health care utilization, health economy

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-09.
Abstract P2-13-09: Pharmacological impact of endoxifen in a laboratory simulation of tamoxifen therapy in postmenopausal breast cancer patients
Authors: Maximov PY , McDaniel RE , Bhatta P , Brauch H , Jordan VC
Published: August 2014

Tamoxifen is a well-established adjuvant drug for the treatment and prevention of Estrogen Receptor (ER) positive breast cancer, effective in both pre- and postmenopausal women. However, the metabolic activation of tamoxifen to endoxifen by the CYP2D6 enzyme system still remains controversial to plan the treatment of patients with breast cancer. Since the discovery and description of the pharmacological properties of endoxifen, clinical trials were undertaken to determine the pharmacological relevance of endoxifen. The results of these trials, however, vary. In this study we demonstrate the pharmacological impact of endoxifen in a laboratory simulation of breast cancer therapy with tamoxifen in postmenopausal women in vitro in a panel of human breast cancer cell lines (MCF-7, T47D, ZR-75-1 and BT474). The concentrations of estrogens (E1/E2) used to simulate postmenopausal women treated with tamoxifen, were obtained from published studies, as well as the concentrations of tamoxifen and its metabolites (N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen) based on the CYP2D6 genotype in postmenopausal breast cancer patients (Murdter TE et al, Clin Pharmacol Ther, 2011). Our results demonstrate that irrespective of CYP2D6 genotype, tamoxifen and its primary metabolites (N-desmethyltamoxifen and 4-hydroxytamoxifen) are able to inhibit completely the estrogen-stimulated growth of breast cancer cells in vitro. Additional endoxifen in any concentration corresponding to CYP2D6 genotype was not able to increase the antiestrogenic effect of tamoxifen and its primary metabolites. Moreover, we demonstrate that 4-hydroxytamoxifen is absolutely essentialforinhibition of estrogen action. Based on our results, we can conclude that endoxifen is pharmacologically supportive but not essential for any genotype of CYP2D6 in a postmenopausal setting. This study (PYM) was supported by Susan G. Komen for the Cure International Postdoctoral Fellowship under Award number SAC100009(VCJ), and the Department of Defense Breast Program under Award number W81XWH-06-1-0590 (VCJ).

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-09.
Abstract P3-01-01: Insulin, Insulin-like Growth Factor-1 and cycling estrogen predict premenopausal mammographic density.
Authors: Frydenberg H , Flote VG , Iversen A , Finstad SE , Furberg A-S , Fagerland M , Wist EA , Schlichting E , Ellison PT , McTiernan A , Ursin G , Thune I
Published: August 2014

Background: Mammographic density, a strong biomarker for breast cancer risk, represents epithelial and stromal proliferation. Insulin and insulin-like growth factor (IGF)-1 are suggested to influence cellular proliferation, while estrogen is a key factor in breast cancer development. However, whether the effects of these hormones among premenopausal women are mediated through mammographic density is less known.

Material and Methods: Fasting serum insulin, IGF-1, and IGF binding protein (IGFBP)-3 were assessed among 202 healthy premenopausal women (Norwegian Energy Balance and Breast cancer Aspects study-I (EBBA-I). Daily salivary levels of 17β-estradiol throughout an entire menstrual cycle were measured at the reproductive Ecology Laboratory, Harvard University, USA. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at day 7–12 of the menstrual cycle. Uni- and multivariable regression models were used to study the associations between hormones and premenopausal percent mammographic density.

Results: Among women with a mean age of 30,7 years, a mean premenopausal percent mammographic density of 29.8 % was observed. Throughout the menstrual cycle when comparing women with a high percent mammographic density (≥28.5%) to women with a low percent mammographic density (<28.5%), we observed insulin, IGF-1 and IGFBP-3 independently and in combination with cycling 17β-estradiol to predict premenopausal percent mammographic density. We observed among women with either serum insulin ≥89 pmol/, IGF-1 ≥24 nmol/l, IGFBP-3 ≥ 100 nmol/l, having a high (≥28.5%) versus a low (<28.5%) percent mammographic density was associated with an increase in overall average 17β-estradiol of 4.0 %, 10.9 % and 14.9%, respectively. Moreover, we observed a higher adjusted Odds Ratio (OR) for having a high percent mammographic density for each standard deviation (SD) increase in overall average 17β -estradiol, insulin, IGF-1 and IGFBP-3: 17β-estradiol, 1.55 (1.06–2.27); insulin, 1.62 (0.76–3.48), IGF-1, 1.90 (1.10–3.27); IGFBP-3, 1.88 (1.05–3.37) (adjusted for age, body mass index-BMI kg/m2)).

Conclusion: Our study supports that insulin, IGF-1 and IGFBP-3 independently, and in combination with cycling estrogen, predicts premenopausal mammographic density. These hormones may be important biomarkers in breast cancer control and clinical practice.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-01-01.