bluuebunny/crossref_metadata_2025_split huggingface dataset:
HAGE (DDX43) protein expression as an independent biomarker of poor clinical outcome of breast cancer (BC) and potential as a therapeutic target for ER-negative BC.
Authors: Chan Stephen , Abdel-Fatah Tarek M. A. , McArdle Stephanie , Moseley Paul , Johnson Catherine , Green Andrew R. , Ellis Ian O. , Rees Robert 
Published: March 2020

1013 Background: Recently, we have confirmed that HAGE is involved in promoting proliferation as assessed by increased thymidine incorporation and our preliminary results using shRNA to permanently knockdown HAGE expression also suggests the involvement of HAGE in tumor motility and metastasis. In this study we aimed to analyze the expression of HAGE in large well-characterized BC cohorts to determine its relationship with other clinico-pathological parameters and to investigate its prognostic value. Methods: HAGE protein expression was assessed in: a) 40 normal breast tissue (NBT), b) 60 invasive BCs and their matching NBT, c) BC cell lines, d) A series of 1650 consecutive cases of primary BC who treated with adjuvant CMF and/or endocrine therapies. Further validation was performed in 2 independent series of high risk ER- BC: a) 300 ER –BC who did not received any CT and b) 396 ER- BC treated with adjuvant anthracycline (ATC) based CT. Results: The NBT showed negative HAGE expression (HAGE-) throughout. HAGE overexpression (HAGE+) was observed in 10% of BC and was significantly associated with aggressive clinico-pathological features including: ER-, high grade and triple negative phenotypes. Moreover, HAGE+ expression showed an adverse outcome with a 2-4 fold increase in the risk of death, recurrence and metastases (ps<0.00001) compared to HAGE-; ps<0.0001. Using a multivariate Cox regression model including ER status, grade, size and tumour stage, HAGE expression was confirmed as a powerful independent prognostic factor (p<0.0001). The poor clinical outcome of HAGE+ was further confirmed in high risk (NPI>3.4) ER- patients who did not received any CT (p<0.0001). While, adjuvant CT either CMF or ATC had a positive impact on HAGE+/high risk ER- BC as HAGE+ had a similar risk of death, recurrence and distant metastases to HAGE- expression. Conclusions: This is the first report which shows HAGE to be a potential predictor for poor prognosis in BC patients, and may be an attractive novel target for molecular and vaccine therapy for those patients. A prospective trial of adjuvant chemotherapy/vaccine to confirm this finding is warranted.
Metformin in early breast cancer (BC): A prospective, open-label, neoadjuvant “window of opportunity” study.
Authors: Niraula Saroj , Dowling Ryan JO , Enis Marguerite , Chang Martin , Done Susan , Hood Nicky , Escallon Jaime , Leong Wey , McCready David R. , Reedijk Michael , Stambolic Vuk , Goodwin Pamela Jean 
Published: March 2020

1019 Background: There is growing evidence that metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. Here, we report final results of a neo-adjuvant “window-of-opportunity” study of metformin in women with operable BC. Methods: Newly diagnosed, untreated, non-diabetic BC patients received metformin 500 mg tid after diagnostic core-biopsy until definitive surgery(no other treatment). Clinical [weight, symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C-30)] and biologic characteristics [insulin, glucose, homeostatic model assessment (HOMA), C-reactive protein (CRP), leptin] were compared pre- and post-metformin as were Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL, an apoptotic marker) and Ki67 (primary end-point) scored blinded by manual count of positive nuclear-staining. The planned sample-size of 40 patients gave 90% power to detect a 5.5 percentage point change in Ki67. Results: Thirty-nine patients were enrolled and mean age was 51 years; metformin was given for 18 days (median), range 13-40 days. Twenty patients had T1 and 19 T2/T3 tumors; 16 tumors were grade III; 24 were N0; 32 ER/PR positive, 5 HER-2 positive. Grade 1-2 self-limiting diarrhea, anorexia and abdominal distention occurred in 50%, 41% and 32%. EORTC QLQ scores were stable in all function domains and overall scores. Main study outcomes are tabulated here. Conclusions: Short-term preoperative metformin was well-tolerated and resulted in clinical and cellular effects in keeping with beneficial anti-cancer effects as demonstrated by improved insulin resistance (HOMA), decreased proliferation (ki67) and increased apoptosis (TUNEL). [Table: see text]
Comparison of molecular (BluePrint+MammaPrint) and pathological subtypes for breast cancer among the first 800 patients from the EORTC 10041/BIG 3-04 (MINDACT) trial.
Authors: Viale Giuseppe , Slaets Leen , De Snoo Femke , van 't Veer Laura J. , Rutgers Emiel J. , Piccart-Gebhart Martine J. , Bogaerts Jan , van den Akker Jeroen , Engelen Kristel , Russo Leila , Dell'Orto Patrizia , Cardoso Fatima 
Published: March 2020

1022 Background: Biology has become the main driver of breast cancer therapy. Intrinsic biological subtypes by gene expression profiling have been identified. Pathology can be used to define surrogates of these subtypes but these are not always concordant, which may lead to different treatment plans. We investigated the concordance between BluePrint (BP) + MammaPrint (MP) (micro array based) breast cancer subtypes and pathological surrogates (based on ER, PR, HER2, and Ki67). Contrary to the Perou gene set (evolved into PAM50), BluePrint was trained using pathological data. Methods: Using available data (centrally assessed pathology and genomic) from the MINDACT pilot phase (Rutgers et al 2011) 621 tumors were analyzed. Two pathology classifications were used: one with 4 categories and one with 5 categories (Goldhirsch et al 2011). Based on BP 3 subtypes are formed: Luminal, HER2 and Basal. The Luminal subtype is further split into Luminal A (MP low risk) and Luminal B (MP high risk). Results: See table. Conclusions: All pathological Basal cases are BP Basal, apart from 1 BP HER2 case. Of the BP Basal cases, 15 are not pathological Basal: 1 is Luminal A, 11 are Luminal B (of which 8 are IHC ER/PR borderline (≥1% and < 10%)) and 3 are HER2. All pathological Luminal (A & B) that are BP HER2 are HER2- by TargetPrint. 25 of the 26 pathological HER2+ that are BP Luminal A are ER+. Most discordant cases are seen within the Luminal subtype, indicating that Ki67 discriminates Luminal A vs. B differently than MammaPrint does. The observed subtype discrepancies reveal potential important impact for treatment-decision making. MINDACT will provide important information. [Table: see text]
Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: Results of the GeparTrio trial.
Authors: Von Minckwitz Gunter , Mueller Berit , Blohmer Jens U. , Kaufmann Manfred , Eidtmann Holger , Eiermann WOLFGANG , Gerber Bernd , Tesch Hans , Hilfrich Joern , Huober Jens Bodo , Fehm Tanja N. , Barinoff Jana , Jackisch Christian , Prinzler Judith , Ruediger Thomas , Erbstoesser Erhard , Loibl Sibylle , Denkert Carsten 
Published: March 2020

1023 Background: We previously reported as a result of the GeparTrio phase III trial that response-guided neoadjuvant chemotherapy (CT) with TACx8 or TAC/NX, compared to TACx6, can improve survival especially in hormone-receptor (HR)-positive tumors. As this benefit could not be predicted by pathological complete response (pCR), better surrogate response markers are warranted. Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC before interim response assessment. Responders were randomized to additional TACx4 or TACx6 and non-responders to TACx4 or NXx4. We centrally measured Ki-67 in1165 pre-CT core biopsies and in 676 post-CT surgical samples. Counting patients with a pCR as having 0% Ki-67, 757 pre-/ post-CT pairs were available. Ki-67 percentage levels were grouped to low (0-15%), moderate (15.01-35%), and high (35.01-100%) according to cut-point finding analysis in a training and validation cohort. Results: pCR rates were 4.2%, 12.9%, and 29.0% in tumors with low, moderate, and high pre-CT Ki-67 levels (p<0.0001). Pre-CT Ki-67 levels significantly predicted disease-free survival (DFS) (log rank p<0.0001) overall, in the HR+ (p<0.0001), but not in the HR- (p=0.5) subgroup. Post-CT Ki-67 levels correlated with DFS (p<0.0001). Patients with low post-CT Ki-67 levels showed comparable outcome to patients with pCR. Patients with increased Ki-67 levels from before to after CT showed an impaired outcome compared to patients with stable or decreased Ki-67 levels (p<0.0001). However, post-CT Ki-67 levels appeared to have more prognostic relevance than Ki-67 changes. Low post-CT Ki-67 levels were not more frequent after response-guided treatments (response-guided vs conventional: p=0.153; TACx6 vs TACx8: p=0.335; TACx6 vs TAC/NX: p=0.420). Similar negative results were found for HR+ and HR- subgroups. Conclusions: Pre-CT Ki-67 levels are predictive for pCR and prognostic for DFS. Post-CT Ki-67 levels and changes between pre-and post-CT-Ki-67 levels are prognostic for DFS. As neither could predict different treatment effects on DFS, Ki67 cannot replace pCR as a surrogate marker for outcome after neo-adjuvant CT.
Association of a compact 13-gene VEGF signature with OS in E2100.
Authors: Willis Scooter , Miller Kathy , Young Brandon F , Perou Charles M. , Hu Zhiyuan , Sparano Joseph , Gray Robert James , Sledge George W. , Davidson Nancy E. , Leyland-Jones Brian 
Published: March 2020

1027 Background: E2100, an open-label, randomized, phase III trial, demonstrated a significant improvement in progression free survival and overall response rate with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. Genentech completed additional clinical trials and submitted these data to the FDA. On 18 Nov, 2011, the FDA Commissioner revoked the agency’s approval of bevacizumab for the breast cancer indication because of the lack of evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. However, the Commissioner “encouraged Genentech to consider additional studies to identify if there are select subgroups of women who might benefit from this drug”. Hu et al. (BMC Medicine 2009) published a compact 13 gene VEGF-signature associated with distant metastases and poor outcomes. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13 gene profile that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. Methods: We have investigated the VEGF signature in silico on Illumina DASL analysis of 122 FFPE samples remaining from E2100. Results: PFS benefit is seen for pacli + bev vs pacli in both treatment arms with the low VEGF signature (HR 0.45 95% CI .27-.77 p .009 n 67) and with the high VEGF signature (HR 0.57 95% CI .32-1.0 p .015 n 55). However, OS benefit is only seen for pacli + bev vs pacli in the high VEGF group (HR 0.56 95% CI .30-1.05 p .02 n 52) and not in patients with the low VEGF signature (HR 1.12 95% CI .66-1.90 p .81 n 67). Conclusions: Hence, this signature, which suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, shows great potential as a predictive biomarker of those patients to whom bevacizumab would convey an OS advantage benefit. We note with great caution that this exploratory analysis of trial subset is underpowered, hence, this compact VEGF signature is being pursued in other bevacizumab trial sets.
Single institution experience with neoadjuvant chemotherapy for metaplastic breast cancer (MBC).
Authors: Kaminsky Anna , Bhargava Rohit , McGuire Kandace P , Puhalla Shannon 
Published: March 2020

1038 Background: Metaplastic breast carcinoma (MBC) is a rare subtype that accounts for <1% of all breast carcinomas. MBC is frequently triple negative and neoadjuvant chemotherapy (NAC) is often used in triple negative breast cancer (TNBC). The objective of this analysis is to ascertain response rates of MBC to NAC as compared to non-metaplastic TNBC. Methods: We searched the Magee Women’s Cancer Center of UPMC IRB-approved neo-adjuvant treatment database which contains outcome data on 594 patients treated from 2004-2010. 116 patients with triple negative breast cancer (ER /PR negative or ER /PR weakly positive (H score of 10 or less) and HER2 negative or indeterminate (HER2 1+ or 2+ without amplification by FISH)), were identified. Nine of these TNBCs had metaplastic subtype and 2 groups were analyzed: metaplastic breast carcinoma (MBC) (N= 9) and non-metaplastic breast carcinoma (NMBC) (N = 107). Tumor volume reduction (TVR), pathologic complete response (pCR), recurrence and mortality were compared in both groups. Results: Mean follow up in MBC group was 43 months and no patients were lost to follow up. Mean tumor size on presentation in MBC group was 4.47 cm while in NMBC group it was 3.33 cm. pCR was noted in 0/9 MBC and 43/107 NMBC cases (p = 0.0253). 6/9 patients had mastectomy, 2/9 had breast conserving surgery (BCS) and 1/9 patients did not have a surgery yet. Average TVR was 28% in MBC cases compared to 74% in NMBCs when cases with pCR were included (p = 0.0001) and 56% when cases with pCR were excluded (p = 0.0202). Follow up on 9 MBC cases revealed 1 recurrence and subsequent death (11%). Follow up on 64 NMBC patients who failed to achieve pCR revealed 22 recurrences (34%) and 18 of them subsequently died (28%).Follow up on 43 NMBC cases that achieved pCR revealed 3 recurrences (7%) and 1 death (2%). Conclusions: MBC was characterized by larger size at baseline as compared to NMBC. There were no pCR’s seen in MBC, but some MBC did achieve response that allowed for breast conservation. Although the average tumor volume reduction was significantly less in MBC compared to NMBC, the NMBC that failed to achieve pCR fared much worse than MBC who did not achieve pCR. Therefore, the triple negative paradox is likely not applicable to MBC.
Association of body mass index and outcome in advanced breast cancer.
Authors: Andreetta Claudia , Driol Pamela , Bonotto Marta , Gerratana Lorenzo , Valent Francesca , Russo Stefania , Minisini Alessandro , Pascoletti Gaetano , Moroso Stefano , Sottile Roberta , Mansutti Mauro , Fasola Gianpiero , Puglisi Fabio 
Published: March 2020

1044 Background: Obesity represents a well-known risk factor for the development of breast cancer and an adverse prognostic factor in early disease. Overweight is associated with reduced efficacy of aromatase inhibitors in adjuvant setting. Few data have been reported about the potential relationship of overweight and outcome in advanced breast cancer (ABC). Methods: We retrospectively evaluated body mass index (BMI) in a consecutive series of 400 ABC patients treated at our institution. BMI was calculated at baseline of diagnosis of ABC. We evaluated association of BMI and other prognostic and predictive markers with Progression Free Survival (PFS) and Overall Survival (OS). We evaluated PFS at first and subsequent lines of chemotherapy (CT) and endocrine therapy (ET). Overweight patients were defined as having BMI > 25. Results: Overweight patients were 52%. Median age of the population was 58 years. Median OS was 33.7 months. Overall, 76% of patients presented with ER+ and 17.7% with HER2+ ABC.Overweight was associated with increased age at diagnosis, menopausal status and luminal B or triple negative immunophenotype. At multivariate analysis, BMI > 25 was associated with better PFS at first-line ET (HR= 0.68, 95% CI 0.46-0.99). BMI was not associated with OS. Conclusions: BMI at baseline does not seem to be an adverse prognostic factor for ABC patients. Overweight may be associated with better PFS in endocrine responsive ABC treated with ET, especially in first-line setting. The role of BMI in ABC deserves to be further investigated.
Impact of biomarkers in predictivity of the efficacy and toxicity of a combination of panitumumab plus FEC 100 followed by docetaxel in a phase II neoadjuvant trial for triple-negative breast cancer (TNBC) patients.
Authors: Nabholtz Jean-Marc A. , Dauplat Marie-Melanie , Abrial Catherine , Weber Beatrice E. , Mouret-Reynier Marie-Ange , Gligorov Joseph , Tredan Olivier , Vanlemmens Laurence , Petit Thierry , Mayer FranÃƒÂ§oise , Jouannaud Christelle , Tubiana-Mathieu Nicole , Kwiatkowski Fabrice , Cayre Anne , Chalabi Nassera , Chollet Philippe J. M. , Penault-Llorca Frederique 
Published: March 2020

1051 Background: We evaluated the combination of a standard chemotherapy with panitumumab as neoadjuvant therapy of operable TNBC. Complete pathologic response (pCR) was the primary endpoint, with toxicity and biologic ancillary studies as secondary endpoints. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Paraffin-embedded samples and frozen samples have been systematically realised before and after neaodjuvant treatment in order to evalutate the biological profile of the tumor. Patients characteristics are : median age 50 ; median tumor size : 40 mm ; invasive ductal carcinoma : 96% ; Scarff-Bloom-Richardson Grade III : 70%, grade II : 30%, ki-67-positive : 100%, EGFR-positive : 78%, cytokeratine5-6-positive : 48% and p53-positive : 59%. Pathological response showed a pCR according to Sataloff’s classification of 52.38% and according to Chevallier’s classification of 46.52%. Skin toxicity was the main side-effect : Cutaneous toxicity grade IV : 5%, grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ; febrile neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade III : 3.3%. Ungueal toxicity grade III : 1.6%, grade II : 20%. Results: We have tested the predictive value of ki-67, EGFR, cytokeratine 5-6 and p53. Only ki-67 is predictive of a pCR according to Chevallier’s classification (p=0.026), with a cut-off of 40% of positive cells (ROC curve): 62% of pCR if ki-67> 40% versus 23% if not (relative risk : 2.7). Low EGFR, high p53, and high cytokeratine 5-6 tended to be associated with poor reponse. No correlations were found between cutaneous toxicities and these biomarkers. The cutaneous toxicities were not predictive. Conclusions: HighKi-67 is predictive of more pCR. High EGFR, low p53 and low cytokeratine 5-6 tended to be associated with better response, but the data are not significant.
Genetic variation in CYP19A1 and response to exemestane: Survival in early breast cancer in the Dutch TEAM trial.
Authors: Houtsma Daniel , Fontein Duveken , Wessels Judith A. M. , Seynaeve Caroline M. , van De Velde Cock JH , Nortier J. W. R. , Guchelaar Henk-jan , Gelderblom Hans 
Published: March 2020

10518 Background: In patients with endocrine-sensitive breast cancer treated with adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a recurrence and who will benefit from AI’s. Variations in the aromatase gene (CYP19A1) are associated with altered estrogen levels and altered aromatase activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 gene on survival in a prospective cohort of breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and who were treated with five years of exemestane were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. A significant association with worse RFS was found with two SNPs: rs7176005 and rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous variant types respectively. These SNPs, as well as a third SNP, rs6493497, were also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). Conclusions: Germline variations in the CYP19A1 gene are related to a worse outcome in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. The relation between RFS and SNP’s in CYP19A1. [Table: see text]
64Cu-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast cancer.
Authors: Tamura Kenji , Kurihara Hiroaki , Yonemori Kan , Takahashi Kazuhiro , Wada Yasuhiro , Hasegawa Koki , Koizumi Fumiaki , Tsuda Hitoshi , Kodaira Makoto , Yunokawa Mayu , Shimizu Chikako , Ando Masashi , Watanabe Yasuyoshi , Fujiwara Yasuhiro 
Published: March 2020

10519 Background: Targeting of HER2 with trastuzumab (T) is a well-established strategy in the metastatic and adjuvant setting in HER2 positive breast cancer (HER2-BC). Although HER2 status is routinely determined using immunohistochemistry or fluorescence in situ hybridization, technical problem can arise when lesions are poorly accessible. HER2 expression can vary during the course of the disease, and there can be discordance in HER2 expression across tumor lesion even in the same patients. Noninvasive HER2 imaging is crucial needed to solve these problems. Previous imaging using 111In or 89Zn- trastuzumab produced high radiation exposure to patients by their long half life (=67.9and 78.4h) and low resolution image. Half life of 64Cu is 12.7h. We performed a feasibility study of the 64Cu-1, 4, 7, 10- tetraazacylododecane-N,N',N",N"'-tetraacetic acid (DOTA)-T to perform PET imaging in patients with HER2-BC. Methods: Patients with HER2-BC received 150 MBq of 64Cu-DOTA-T and underwent PET scan 1, 24 and 48h after the injection. Six patients were evaluated internal dosimetry by collecting radioactivity data of blood and normal tissue in each time point from PET study, and radiation exposure by collecting clothes, linen and urine to test feasibility for outpatients. Results: Fifteen patients who received T therapy were enrolled in the “first-in-human” trial. All patients had no severe toxicity. Radiation excretion evaluating clothes, linen were under background level. Radiation exposure of 64Cu-DOTA-T was equivalent to that of conventional 18F-FDG-PET. Distribution of liver, kidney, spleen, and blood vessel was 2-8 SUV, and uptake in other normal tissue was low. At visual examination, in two patients brain metastases were clearly visualized by 64Cu-DOTA-T-PET, suggesting that there are disruptions of the blood-brain barrier at the site of the brain metastases. The sternum bone metastasis was well visualized and quantitatively monitored according to the response by T. Primary breast cancers, lymph node metastases and lung metastases could also be visualized at the lesion indentified by CT. Conclusions: 64Cu-DOTA-T-PET was feasible test even for outpatient, and provides specific and high resolution image in HER2 positive lesion.