bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer
Authors: Park IH , Lee KS , Im S-A , Jung KH , Park KH , Im Y-H , Lee S , Kim YJ , Kim H-J , Lee S , Lee MH , Kim T-Y , Lee K-H , Kim S-B , Ahn J-H , Nam B-H , Ro J 
Published: August 2014

Abstract
Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC.
Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.
Abstract P1-01-02: The SentiMag study: Sentinel node biopsy with superparamagnetic iron oxide vs. radioisotope
Authors: Thill M , Kurylcio A , Blechmann R , van Haasteren V , Grosse B , Berclaz G , Polkowski W , Hauser N 
Published: August 2014

Abstract
Background:
The SentiMag study compares the “gold standard” 99mTc with a new technique, which employs superparamagnetic iron oxide particles (SPIO) for localization of sentinel lymph nodes. Aim of this study is to investigate the potential equivalency of the SentiMag® technique in comparison to the gold standard of sentinel lymph node biopsy (SLNB).
Materials and methods:
In a prospective, multicentre and multinational 2-arm study, 150 patients with histologically verified breast carcinoma are examined. For comparison, SLNs are marked initially with radioisotope following a 1- or 2-day protocol. Additionally, SPIO (Sienna+®) is injected in the operation room by the surgeon at least 20 minutes before SLNB into the subareolar interstitial tissue, followed by 5 minutes massage. SLN-detection is carried out using a magnetometer (SentiMag®) and a gamma probe. Preparation and excision of lymph nodes is conducted using both techniques in a parallel manner. All lymph nodes marked with either tracer are excised.
Results:
Interim analysis of 138 patients resulted in a detection rate concordance per patient of 97% (134/138). An average of 1.9 (radioisotope) and 2.0 (SPIO) lymph nodes were collected per patient. Nodal detection rate was 92% (250/273) for the radioisotope vs. 97% (265/273) for the SPIO tracer with magnetometer detection. The proportion of pathologically positive lymph nodes was 38/250 (15%) vs. 39/265 (15%) for the radioisotope and the SPIO tracer respectively. All pathologically positive lymph nodes detected with the conventional technique (radioisotope) were also detected with the new technique (SentiMag®).
Conclusions:
The SentiMag® provides an easy technique which can be rapidly implemented into daily routine. Due to the simple handling, preoperative efforts can be reduced to a minimum. If further and consistent results prove its efficacy, this technique may ultimately replace the standard of care.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-02.
Abstract P1-02-02: Concordance of microarray based determination of ER, PR and HER2 receptor status and local IHC/FISH assessment in the prospective neo-adjuvant breast registry symphony trial (NBRST)
Authors: Beitsch P , Gittleman M , Akbari S , Stork-Sloots L , de Snoo F , Gibson J , Whitworth P 
Published: August 2014

Abstract
Background
The level of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression is predictive for prognosis and/or treatment response in breast cancer patients. However, differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of the results. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2. Previously TargetPrint was shown to be strongly correlated with high quality IHC/FISH assessment, especially for ER and HER2. Concordance rates were 98% (k = 0.90) for ER; 85% (k = 0.62) for PR and 96% for HER2 (k = 0.78) in 619 patients (Viale et al., SABCS 2011).
This study compares results from the microarray-based TargetPrint with IHC and FISH conducted according to local standard procedures in the prospective NBRST study.
Methods
The NBRST study includes women aged 18–90 with histologically proven breast cancer, who are scheduled to start neo-adjuvant chemotherapy (CT) or neo-adjuvant endocrine therapy (ET), and who provide written informed consent. The mRNA level of ER, PR and HER2 (TargetPrint) was assessed at the Agendia laboratory (Agendia Inc, Irvine, CA) in fresh and formalin fixed paraffin embedded tumor samples submitted from 40 institutes in the US. The results of the IHC/FISH assessments conducted according to local standard procedures were compared to the quantitative gene expression readouts.
Results
There were 355 eligible patients enrolled. 67% of patients are IHC ER positive and 25% Her2 IHC/FISH positive. 11 patients were IHC/FISH HER2 equivocal (all TargetPrint HER2 negative). Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 88% (k = 0.75)for ER; 83% (k = 0.66) for PR and 89% (k = 0.70) for HER2. The discordance range for institutes who submitted more than 10 samples was 0-30% for ER, 0-47% for PR and 0-28% for HER2. 16% of all IHC ER+ samples were classified negative by microarray. In contrast, 4% of IHC ER- samples were classified positive by microarray. However for HER2, as many as 33% of IHC/FISH HER2+ samples were classified negative by microarray; 3% of IHC/FISH HER2- samples were classified positive by microarray.
Conclusions
Microarray based readout of ER, PR and HER2 status using TargetPrint is comparable to local IHC and FISH analysis in 355 analyzed samples from 40 US institutes but the discordance range for individual institutes was up to 30% for ER and 28% for Her2.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-02.
Abstract P1-05-01: Characterization of human postpartum breast involution: Implications for young women’s breast cancer
Authors: Borges VF , Jindal S , Gao D , Bell P , Edgerton SM , Ambrosone CB , Thor AD , Schedin P 
Published: August 2014

Abstract
Introduction: Women diagnosed with breast cancer within 5 years postpartum have poor outcomes. In rodents, postpartum mammary gland involution promotes tumor progression and metastasis, implicating breast involution in the poor prognosis of breast cancers diagnosed in postpartum women. Rodent mammary gland involution is characterized by wound healing programs that include epithelial cell death, immune cell infiltrate, and fibrillar collagen deposition; all attributes associated with breast cancer progression. Thus, the gland remodeling of postpartum involution may provide a plausible explanation for how postpartum breast involution promotes breast cancer. Here, we characterize human breast tissue across pregnancy, lactation, and the postpartum time-period to determine if remodeling of the secretory competent breast to a quiescent state involves loss of secretory lobules, and whether involution is mediated by wound healing-like programs.
Methods: Adjacent normal breast tissues from pre-menopausal women (n = 140), aged 20-45 years, were grouped by reproductive categories of never-been-pregnant (NBP), pregnant, lactating, and by time since last delivery, and evaluated histologically and by special stain for epithelial area, lobular subtype composition, apoptosis, immune cell infiltration, and collagen deposition, using computer assisted quantitative methods. Statistical comparisons between multiple categories were done using one way ANOVA.
Results: Dramatic increases in breast epithelial area and lobule differentiation were observed, with 5-8 fold increases for pregnancy and 10-13 fold for lactation, over nulliparous controls. By 12 months postpartum, epithelial content and lobular differentiation were indistinguishable from nulliparous controls, consistent with complete regression of the lobular structures developed in preparation for lactation. Analyses of apoptosis, immune cell infiltration, and collagen deposition confirmed human postpartum breast involution is characterized by wound healing-like, tissue remodeling programs.
Conclusion: Human postpartum breast involution is a dominant tissue-remodeling process that returns the gland to a morphological state largely indistinguishable from the never-been-pregnant gland. Further, involution occurs within a defined window of time. Our data implicate postpartum breast involution as window of risk for breast cancer progression and suggest a rational window for intervention.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-01.
Abstract P1-05-02: COX-2 expression in normal mammary epithelium is estrogen responsive and predicts expression in DCIS and invasive ductal carcinoma
Authors: Schedin P , Fornetti J , Jindal S , Borges V 
Published: August 2014

Abstract
Background: Cyclooxygenase-2 (COX-2) overexpression is implicated in the poor prognosis of young women's breast cancer. Understanding the regulation of COX-2 expression in normal premenopausal breast tissue and its relationship to malignancy is anticipated to provide insight into COX-2 as a potential therapeutic target for young breast cancer patients.
Methods: To investigate COX-2 regulation and expression, quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 83 premenopausal women with known clinical reproductive histories as well as on rat mammary glands with distinct estradiol and progesterone exposures. To determine the stability of COX-2 expression over time, a small cohort of women with serial breast biopsies 2-3 weeks apart was evaluated.
Results: COX-2 expression in normal adjacent breast tissue was predominantly epithelial, varied &gt;40-fold between individual women, and was independent of proximity to tumor and tumor biology. COX-2 upregulation occurred in alveoli during pregnancy and with estradiol and progesterone exposure in the rat. Though these data demonstrate ovarian hormone regulation, COX-2 expression was relatively stable for each individual premenopausal woman over a 2-3 week assessment window. Furthermore, COX-2 expression levels in normal epithelium independently predicted COX-2 expression levels in tumors.
Conclusions: COX-2 expression in the adjacent normal breast epithelium is highly variable across premenopausal women, and may be further modified by ovarian hormone exposure. Moreover, COX-2 expression in the normal breast independently predicts COX-2 expression in tumors, implicating women with high COX-2 expression in the normal breast epithelium as high risk patients who may benefit from COX-2 inhibitor therapy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-02.
Abstract P1-06-13: Periostin controls cytokine production to maintain breast cancer stem cells
Authors: Lambert AW , Ozturk S , Papageorgis P , Abdolmaleky H , Thiagalingam S 
Published: August 2014

Abstract
Recent evidence suggests that the molecular heterogeneity inherent to breast cancer, which underlies metastasis, resistance to treatment and disease recurrence, can be driven by a distinct subpopulation of tumor cells referred to as cancer stem cells (CSCs). Basal-like breast cancer represents a particularly aggressive disease subtype and the tumor cells share phenotypic similarities to breast cancer stem cells. However, the extracellular cues and intracellular pathways that CSCs rely on remain unclear. Working with a breast cancer progression model system we found the invasive breast cancer cell line to exhibit numerous stem-like characteristics. Gene expression profiling, along with a careful review of the literature, identified a secreted extracellular matrix molecule, periostin (POSTN), which we hypothesized to be required for the maintenance of a cancer stem cell state. POSTN expression was increased in numerous basal-like breast cancer cell lines, as well as in cells grown as mammospheres and in the CD44+/CD24- fraction of tumor cells. Furthermore, CSC-like lines displayed increased surface levels of the integrin alpha-v beta-3 heterodimer, a known receptor for POSTN, suggesting that hyperactivation of a POSTN signaling axis could potentially regulate the CSC state. Using stable cell lines expressing an shRNA directed at POSTN or ITGB3 we have found that POSTN signaling is required for efficient mammosphere formation and for the maintenance of an ALDH-positive CSC population. Disruption of this signaling axis resulted in decreased production of cytokines, including IL-6 and IL-8 - known regulators of CSCs - as well as downstream STAT3 signaling. Furthermore, high POSTN expression is associated with a worse clinical prognosis in ER-negative breast cancer. Therefore, we suggest that POSTN signaling through integrin receptors may enrich for highly tumorigenic breast CSCs in a subset of basal-like tumors, leading to aggressive and recurrent malignancies. This reveals a previously unknown link between POSTN signaling and cytokine production, and suggests that basal-like cancers can establish a microenvironmental niche supportive of cancer stem cells.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-13.
Abstract P1-08-09: EGFR expression is associated with decreased response from HER2 targeted therapeutics in the neo-adjuvant setting in the NeoALTTO trial
Authors: Rimm DL , Holmes E , Schalper K , Bradbury I , Zarrella E , Ellis C , Baselga J , Eidtmann H , Piccart M , Harbeck N , Pusztai L , Perez E 
Published: August 2014

Abstract
Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may modulate the effectiveness of trastuzumab or lapatinib. Historically, it has been difficult to measure, but recently we reported a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody which showed that high levels of EGFR were associated with decreased benefit in the concurrent arm of the North Central Cancer Treatment Group (NCCTG/Alliance) N9831 trial (Rimm et al, SABCS 2012). Here we assess its value in the neo-adjuvant setting in the NeoALTTO trial.
Methods: NeoALTTO randomized 455 breast cancer patients to neoadjuvant trastuzumab, lapatinib or both and showed benefit in both single anti-HER2 therapy arms, and the combination therapy showing about twice as much benefit as either single drug arm. We used the previously described AQUA method of quantitative immunofluorescence to measure EGFR levels using the D38B1 antibody on between 4 and 140 fields of view per slide on 353 specimens. The averaged EGFR score was standardized to the absolute concentration using cell lines and western blots and the 13 ng/ug total protein established in the N9831 trial was tested to determine predictive value for pathological complete response (pCR) defined as ypT0/is.
Results: In NeoALTTO, 19% of the patients had EGFR levels above 13 ng/ug, compared to 16% in NCCTG N9831. The pCR rate was 35.3% in the patients with low EGFR, compared with 29.8% for high EGFR but this difference was not statistically significant. However, when adjusted for treatment and hormone receptor (HR) status, high EGFR is statistically significantly associated with lower response rate(p = 0.038). Continuous analysis measures were not significant. The effect on overall response at 6 weeks was also weakly significant when adjusting for treatment and HR status (p = 0.06). Surprisingly, for HR negative patients in the lapatinib only arm, the pCR rate in the low EGFR group was 47.2% compared with 16.0% in the high group. While this difference is statistically significant (p = 0.014), it should be interpreted cautiously because of the small numbers of patients and the multiple tests performed.
Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased pCR rate from HER2 targeted therapy in the neoadjuvant setting. This observation is consistent with NCCTG N9831. Although underpowered, high EGFR levels predicted decreased pCR rate from lapatinib, the opposite of that anticipated for this small molecule dual EGFR/HER2 inhibitor. Further studies are required to determine the clinical utility of this assay and the biological mechanisms underlying these observations.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-09.
Abstract P1-08-17: Impact of claudin-3 and basal-markers expressions on pathological complete response to neoadjuvant chemotherapy and prognosis in triple negative breast cancer
Authors: Nogi H , Kamio M , Kato K , Toriumi Y , Suzuki M , Uchida K , Takeyama H 
Published: August 2014

Abstract
Background
Triple negative breast cancer (TNBC) has responded well in the neoadjuvant setting, with rates of pathologic complete response (pCR) commonly higher than for other breast tumor types. However, more than half of TNBC patients do not achieve a pCR and have a very poor prognosis. Cluster analysis identified 6 TNBC subtypes displaying unique gene expression, including basal-like and a mesenchymal stem-like (claudin-low) subtype. The object of this study was to evaluate the clinical utility of claudin-3 and basal-markers expressions in the prediction of pCR and prognosis in a cohort of breast cancer patients receiving the combination of taxane and anthracycline as neoadjuvant chemotherapy.
Materials and Methods
A prospective data base of 412 Japanese women with stage I/II/III breast cancer who received neoadjuvant chemotherapy was analyzed. The regimens were 6 cycles of concurrent administration of doxorubicin (50 mg/m2) and docetaxel (60 mg/m2) or 4 cycles of epirubicin (100 mg/m2), 5-fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). We performed immunohistochemical staining for ER, PgR, HER2, epidermal growth factor receptor (EGFR), cytokeratin 5/6 and claudin-3 using specimens obtained at diagnosis by core needle biopsy. Based on immunoreactivity, TNBC tumors were classified into basal/claudin-high (BCH), basal/claudin-low (BCL), non-basal/claudin-high (NBCH) and non-basal/claudin-low (NBCL).
Results
The overall pCR of this patient cohort was 19%. pCR was observed 30 cases of 84 TNBC (36%) and 50 cases of 328 non-TNBC (15%)(p&lt;0.0001). Among the TNBC tumors, pCR rate was significantly different between subgroups. BCH 50%, BCL 23%, NBCH 83% and NBCL 43% (p = 0.039). The 5-year overall survival rate was significantly different between TNBC and non-TNBC. TNBC 81% and non-TNBC 94% (p = 0.0017). The 5-year overall survival rate was different between triple-negative subgroups. BCH 92%, BCL 78%, NBCH 83% and NBCL 46%.
Conclusions
This study indicated that claudin-3 and basal-markers might be predictive biomarkers of pCR and prognosis in triple negative breast cancer patients treated with neoadjuvant chemotherapy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-17.
Abstract P1-08-21: Detection and monitoring of circulating endothelial cells, circulating tumor cells and disseminated tumor cells during neoadjuvant breast cancer treatment including bevacizumab
Authors: Mathiesen RR , Borgen E , Sætersdal AB , Fangberget A , Schirmer C , Stav I , Fagerland MW , Wist E , Engebråten O , Naume B 
Published: August 2014

Abstract
Background: Results from studies with bevacizumab in addition to traditional neoadjuvant therapy (NAT) indicate a need for predictive biomarkers. As a sub-study of the NeoAva study (a neoadjuvant study), the aim was to investigate the potential association between the presence of circulating endothelial cells (CECs) in peripheral blood (PB), circulating tumor cells (CTCs) in PB and disseminated tumor cells (DTCs) in bone marrow (BM) at different time points during NAT +/- bevacizumab and at one year follow-up, and therapy response.
Patients and methods: A total of 150 HER2-negative patients with cT2-4 (≥ 2.5cm) N0-3 M0 status were randomized to receive NAT with or without bevacizumab. In this sub-study, 90 patients have so far been analyzed. Of these, 82 received chemotherapy (FEC100→taxane) and 8 received endocrine therapy (letrozole) + / - bevacizumab. Therapy response was evaluated according to the RECIST criteria and achievement of pathological complete response (pCR). Number of CECs, CTCs and DTCs were assessed at baseline after 12 weeks, at surgery (after 24 weeks) and at one year follow-up. Blood samples were analyzed by CellSearch® to assess CEC and CTC counts. The detection of DTCs was performed by immunocytochemical analysis of 2 × 106 BM mononuclear cells.
Results: The pathological complete response rate was 10 out of 90 (11.1%), eight of these patients received bevacizumab. For bevacizumab-treated patients with a change in CEC counts from baseline to time of surgery below median change (27 CECs), 35% (6/17) achieved pCR compared to 6% (1/18) in the group with a CEC count-increase above median change (p = 0.035). The corresponding pCR rates for patients not receiving bevacizumab (median CEC change 131 CECs) were 0% (0/15) and 13% (2/14), respectively. Stepwise testing of thresholds for CEC changes in the bevacizumab-arm revealed significant associations to pCR for change-values between 20 and 40. CTC- and DTC-status or -changes were not associated with tumor response or CEC changes.
Conclusion:
The presented results indicate that the level of change in the number of circulating endothelial cells during neoadjuvant therapy including bevacizumab is associated with the pathological complete response rate in breast cancer patients. This supports additional testing of CECs as a surrogate marker for response to this treatment. The analyses will be up-dated with results from the rest of the included patients.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-21.