bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-09-05: Risk Group Selection in Primary Breast Cancer According to ASCO Recommended Biomarkers Onkotype DX and uPA/PAI-1: First Experience from Prospective Multicenter WSG Plan B Trial
Authors: Degenhardt T , Gluz O , Thomssen C , Vetter M , Kates R , Warm M , Shak S , Augustin D , Kusche M , Untch M , Paepke S , Uleer C , Dünnebacke J , Nitz U , Harbeck N 
Published: April 2011

Abstract
Background: Both the Oncotype DX multi-gene assay and invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy in primary breast cancer (BC). Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is evaluating anthracyline-free adjuvant chemotherapy (6x TC) vs. standard 4xEC-4xDOC in HER2- negative BC with 0-3 positive lymph nodes, Oncotype DX is used as selection criterion where pts with RS&gt; 11 are randomized to one of the two chemotherapy arms and pts with RS ≥11 treated with hormonal therapy alone. uPA/PAI-1 (both low vs. either/both high), measured by ELISA, is obtained as an optional risk factor. Results: By June 2010, 1064 patients had been randomized in Plan B (96 recruiting centers). In 153 patients (27 centers), uPA and PAI-1 had been measured; for 131 (84 N0, 47 N+) of these, Oncotype DX Recurrence Score® (RS) results were also available. When considered as continuous variables, RS was weakly positively correlated (Spearman's coefficient) with uPA (rs=0.18, p=0.04) and with PAI-1 (rs=0.23, p=0.01). When considered as risk categories/(Table 1), there was a weak concordance between RS and uPA/PAI-1, using either the standard RS cutoff points (18 and 30) or the TAILORx trial cutoff points (11 and 25).
Table T: Association between RS and uPA/PAI-1 categories
Assignment of high risk was most strongly concordant between uPA/PAI-1 and RS (RS &gt; 25: 22/25 patients had high uPA/PAI-1; RS &gt;30: 14/15 patients had high uPA/PAI-1). This high-risk concordance extends to N0 patients (RS&gt;25: 17/19 N0 pts had high uPA/PAI-1; RS&gt;30: 11/12 pts had high uPA/PAI-1). Discussion: For the first time, risk groups in primary breast cancer according to both Oncotype DX and uPA/PAI-1 have been compared. These preliminary data show that the high RS group seems highly concordant with the prospectively assessed invasion markers uPA/PAI-1. However, within low and intermediate RS, uPA/PAI-1 could still identify a substantial collective at risk; low uPA/PAI-1 could define a clinically relevant low-risk collective within risk groups that would be classified as “intermediate” according to the multigene assay Oncotype DX. Additional recruitment and outcome assessment of the ongoing multicenter WSG Plan B trial will address the clinical significance of these findings.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-05.
Abstract P2-09-07: Elevated Pretreatment Serum CA9 (CAIX) (Carbonic Anhydrase 9) Predicts Reduced Progression-Free and Overall Survival in Trastuzumab-Treated Metastatic Breast Cancer
Authors: Anyanwu UI , Hou HY , Shrinvastava V , Evans M , Leitzel K , Ali SM , Koestler W , Fuchs E-M , Brown-Shimer S , Ramirez J , Hamer P , Carney W , Kalu R , Repich K , Rizvi S , Lipton A. 
Published: April 2011

Abstract
Background: Approximately one-half of HER2-positive breast cancer patients will respond to first-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Serum HER2, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), CA9, Insulin-like growth factor-1 receptor (IGF-1R), VEGF-165, and endoglin were measured using ELISA assays in 60 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The HER2, TIMP-1, uPA, CA9, IGF-IR, and VEGF-165 ELISAs were from Oncogene Science/Siemens Healthcare Diagnostics, Cambridge, MA; and the endoglin ELISA was from R&D Systems, Minneapolis, MN. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables.
Results: Pretreatment serum HER2 (p= 0.008), TIMP-1 (p&lt; 0.0001), uPA (p= 0.006), endoglin (p= 0.010), and CA9 (p &lt;0.0001) were all significant as univariate continuous biomarkers for predicting PFS to first-line trastuzumab-containing therapy, but VEGF (p=0.94) and IGF-IR (p=0.11) were not. In multivariate analysis for PFS with all 7 biomarkers, only serum CA9 (p= 0.002) was a significant independent covariate. For OS, pretreatment serum HER2 (p= 0.018), TIMP-1 (P&lt;0.0001), uPA (P&lt;0.0001), endoglin (0.006), CA9 (P&lt;0.0001) were all significant as univariate continuous biomarkers for prognosis, but VEGF (p=0.69) and IGF-IR (p=0.098) were not. In multivariate analysis for OS with all 7 biomarkers, only serum CA9 was a significant independent prognostic covariate (p=0.001), and TIMP-1 trended significant (p=0.069). Conclusions: Elevated pretreatment serum CA9 (a marker of hypoxia) predicts reduced progression-free survival and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-07.
Abstract P2-09-09: Loss of BTG2 Expression in Breast Cancer Predicts Tamoxifen Resistance
Authors: Takahashi M , Hayashida T , Sakata M , Jinno H , Kitagawa Y. 
Published: April 2011

Abstract
Background: The B-cell translocation gene-2 (BTG2) belongs to a class of proteins known as the Tob and BTG anti-proliferative protein family. It was shown that estrogen and progesterone suppress BTG2 mRNA for the development of mammary gland. (Kawakubo et al., Oncogene 2004) Expression analysis of BTG2 protein in estrogen receptor (ER) positive human breast cancer was revealed the loss of nuclear expression in 46% of tumors and showed a significant inverse correlation with cyclinD1 expression. (Kawakubo, Hayashida et al., Cancer Res 2006) According to the Oncomine database online, loss of BTG2 expression significantly correlated with increased recurrence rate after tamoxifen monotherapy. Based on these results, we hypothesized that BTG2 expression might be a novel biomarker for predicting the clinical outcome in tamoxifen treatment and analyzed if BTG2 expression affects the sensitivity against tamoxifen both in vitro and in vivo.
Method and Results: The cohort of 60 patients treated with adjuvant tamoxifen monotherapy was available online. (Ma et al., Cancer Cell 2004) Comparison of disease-free survival (DFS) of patients whose laser-captured tumors showed positive BTG2 expression versus patients with loss of BTG2 expression revealed an univariate association in the dataset. (log-rank probability, p=0.029) Multivariate analysis indicated that BTG2 resulted independent prognostic factor for DFS (HR, 0.69; 95% CI, 0.495 to 0.963; p=0.029).
In vitro cellular proliferation assay to evaluate the cytotoxicity induced by tamoxifen against ER positive cell lines revealed that endogenous BTG2 positive cell line, MCF7 and T47D, showed drug sensitivity, whereas MDA-MB468 expressing loss of BTG2 showed tamoxifen resistance. (MCF7; IC50=7.35uM, T47D; =3.79uM, MDA-MB468; &gt;25.0uM) Tetracycline-inducible BTG2 expression model in MCF7 was developed to assess the cytotoxicity by tamoxifen treatment under the condition of BTG2 overexpression in vitro and in vivo. The cellular proliferation was strongly inhibited by the concomitant administration of tetracyclin and tamoxifen in vitro. The cell line was injected into the mammary fad pad of immunodeficient mice and these were administered water including tetracyclin and/or tamoxifen pellet at the time when the xenografted tumor grew to be over 125mm3 for 3 weeks. The transgene expression was confirmed by both RT-PCR and immunohistochemistry. Tumor growth ratio was significantly suppressed in the concomitant administration of tetracyclin and tamoxifen in comparison with single treatment of tamoxifen or of tetracyclin. Consistently, tumor weight and Ki67 expression were also significantly suppressed in the mice administered both tamoxifen and tetracyclin.
Conclusion: Despite further validation studies need to be conducted, BTG2 expression may be useful biomarker to identify patients appropriate for tamoxifen treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-09.
Abstract P2-09-11: Response of Invasive Lobular Cancers to Neoadjuvant Therapy
Authors: Mukhtar RA , Hwang ES , Livasy C , Esserman LJ. 
Published: April 2011

Abstract
Background
Invasive lobular carcinoma (ILC) makes up 10-15% of all breast cancer. While neoadjuvant therapy (NAC) is increasingly used in locally advanced invasive cancers, some evidence suggests that ILC does not respond to NAC. The I-SPY trial has shown an association between expression of high risk gene signatures and increased pathologic complete response (pCR) to NAC. We hypothesized that compared to invasive ductal carcinoma (IDC), ILC would have decreased expression of high risk gene signatures, and decreased rates of pCR. Methods
We analyzed data from 221 patients in the I-SPY trial, a prospective, multicenter neoadjuvant breast cancer trial with serial pathology, imaging, and expression arrays. A dedicated breast pathologist at each site reviewed histology, and e-cadherin staining was performed centrally on cases identified as ILC. We compared rates of wound healing signature activation, NKI (Netherlands Cancer Institute) profile status, and proportion of pCR in ILC compared to IDC. Other comparisons were the presence of p53 mutations, molecular subtype, and MRI phenotype. We used the chi-squared test, Fisher's exact test, and Student's t-test for comparisons. Results
Of 221 patients, histology on core biopsy was ductal in 195 (88%), lobular in 18 (8%), and mixed ducto-lobular in 8 (3.6%); the last cases were included in the IDC group. ILC and IDC cases were similar by tumor size, age at diagnosis, and race. Expression array data were available on 12 of 18 (67%) ILC and 149 of 203 (73%) IDC. The proportion of p53 mutations, basal subtype and NKI high risk did not differ significantly. However, ILCs were significantly less likely to express the activated wound healing signature compared to IDCs (50% vs 80%, p = 0.03) and had different imaging phenotypes, with most ILCs appearing multinodular or diffuse on MRI (p = 0.028). Three of 18 (17%) ILCs had a pCR, compared to 55/197 (28%) IDCs. Of the 18 ILC, 11 of 15 tested were e-cadherin negative (73%). Of 18 ILCs, 16 (89%) were hormone receptor (HR) positive, and comparison to HR+ IDC showed similar rates of pCR in the two groups (19% pCR in HR+ ILC vs 14% pCR in HR+ IDC). There was no significant difference in expression of the activated wound healing signature when comparing ILCs to HR+ IDC. Conclusions
There is significant heterogeneity within ILC, such that no one molecular subtype or genetic expression signature identifies all ILCs. The rates of pCR among ILC are similar to those seen in HR+ cancers. Although larger studies are needed to confirm these findings, we saw no evidence that ILC differs from IDC in response to NAC.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-11.
Abstract P2-09-16: Effect of Continuous Statistically Standardized qPCR and IHC ER and PR on Disease-Free Survival in NCIC CTG MA.12
Authors: Chapman J-AW , Nielsen T , Ellis MJ , Bernard P , Chia S , Gelmon K , Pritchard KI , Le Maitre A , Shepherd L , Bramwell V. 
Published: April 2011

Abstract
Background: Inter-laboratory comparability of ER and PR assay results has been problematic for decades. Statistical standardization has been proposed as an adjunct following good laboratory quality control. We demonstrate this process for ER and PR centrally assessed by qPCR and IHC. Methods: NCIC CTG MA.12 is a placebo-controlled trial of tamoxifen therapy following adjuvant chemotherapy in premenopausal women with early breast cancer. 672 women were accrued, 505 of whom had locally determined ER and/or PR positive tumours. ER was centrally assessed by qPCR and IHC for respectively 385 and 392 patients, and by PR, for 389 and 376. The effects on DFS of continuous 1) log2 (qPCR) and 2) ln (IHC % positive stain) in statistically standardized units were investigated for all women with all lab results, and in the subgroup with IHC ER+ and/or PR+ tumours.
DFS is defined as the time from randomization to recurrence or death. Multivariate examinations were with adjusted Cox regression, with adjustment by stratification factors nodal status and chemotherapy type; ER and PR had forced inclusion in models, while trial therapy and baseline patient characteristics were added in step-wise mode (p&lt;=0.05). Unvariate tests were with adjusted log-rank statistic and Kaplan-Meier plots for ER and PR (ER and PR 0; standardized cut-points for ER and PR with positive stain of &lt;= 1.0; &gt; 1.0, &lt;= 0.0; &gt; 0.0, &lt;= 1.0; &gt;1.0). Results: Median follow-up for the MA.12 trial was 9.7 years. Univariately, qPCR ER was not associated with DFS (p=0.19), while both qPCR PR (p=0.09) and IHC ER (p=0.08) had weak evidence of association, and IHC PR had p=0.04. Multivariately, patients randomized to tamoxifen had significantly better DFS (p=0.002-0.005) in all patients assessed and in those with ER and/or PR &gt; 0; ER and PR by qPCR and IHC were not associated multivariately with DFS (P&gt;0.05). ER and PR were not associated with DFS (P&gt;0.05) for those who received tamoxifen, while qPCR ER and/or PR, and IHC ER were inconsistently associated with DFS for those on the placebo arm.
Conclusions: In this subgroup of centrally assessed MA.12 patients, trial therapy was significantly associated with DFS. Similar non-significant multivariate results were obtained multivariately with statistically standardized, continuous qPCR and IHC ER and PR. We plan to further investigate adjunctive statistical standardization in larger NCIC CTG trials.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-16.
Abstract P2-09-18: High VEGFR1 and VEGFR3 Protein Expression Is Associated with Improved Response to the Combination of Paclitaxel (P) and Bevacizumab (Bev) Therapy in Patients with HER2-Negative Metastatic Breast Cancer (MBC)
Authors: Papadimitriou C , Kourea H , Papazisis K , Christodoulou C , Res E , Papakostas P , Petraki K , Bafaloukos D , Razis E , Fountzilas G. 
Published: April 2011

Abstract
Background: Treatment with weekly P and 2-weekly Bev has been established as an active 1st line treatment in patients with MBC. However, robust predictive or prognostic biomarkers for this treatment have not been identified as yet.
Patients and Methods: In this retrospective analysis, we evaluated the activity of this combination in patients with HER2-negative MBC. Further, we explored the role of a panel of biomarkers on patients’ outcome. VEGF-A, VEGF-C, VEGFR1, VEGFR2, and VEGFR3 were centrally assessed by immunohistochemistry (IHC) in 70 tissue blocks. P was administered either weekly 90 mg/m2 x12 with 2-weekly Bev 10 µg/kg (86 patients) or 3-weekly 175 mg/m2 x6 with 3-weekly Bev 15µg/kg (38 patients). Bev was administered until progression in the majority of the patients.
Results: The ORR did not differ significantly between the weekly or 3-weekly P schedule (55.8% vs 55.3%). In contrast to the published literature with P monotherapy, median PFS was significantly longer in the 3-weekly compared to the weekly P schedule (20.4 months vs 10.2 months, p=0.029). Median survival has not been reached yet. 2-year survival was 76.1% and 67.3%, respectively (p=0.085). High VEGFR1 and VEGFR3 protein expression, assessed by IHC, was associated with higher response rates (p=0.010 and p=0.039, respectively).
Conclusions: This retrospective analysis confirmed the activity of P and Bev in patients with HER2-negative MBC. Protein expression of VEGFR1 and VEGFR3 was found to be of predictive value. These findings need to be validated in a larger cohort of patients treated with this combination. VEGF polymorphisms (VEGF-2578 and VEGF-1154) are currently assessed in peripheral blood DNA from our patients for possible predictive value.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-18.
Abstract P2-09-27: Predictive Factors of Complete Axillary Downstaging after Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Vidal M , Perez-Garcia JM , Muñoz E , Saura C , de Mattos L , Gomez P , Cortes J , Baselga J , Bellet M. 
Published: April 2011

Abstract
Background: The axillary status after neoadjuvant chemotherapy (NACT) is an important prognostic factor. Complete axillary downstaging (CAD) occurs in up to 20-30% of the patients, however, sentinel node biopsy after NACT is not recommended in patients with initial axillary nodal involvement and complete axillary response after NACT. Our aim was to investigate predictive factors of CAD after NACT to identify patients who could avoid an unnecessary axillary dissection. Patients and methods: From January 2004 to December 2008, 256 consecutive patients were diagnosed with invasive breast cancer and received NACT and breast surgery at our institution. Patients were eligible for this analysis if they met the following inclusion criteria: clinically and/or cytologically proven metastatic axillary nodes; complete axillary response after NACT; and complete axillary dissection after systemic treatment. CAD was defined as pN0 (isolated tumor cells and micrometastasis were excluded). Univariate and multivariate analyses were performed to assess the association between CAD and either tumor characteristics or intrinsic cancer subtypes.
Results: 84 patients were included. Median age was 51.64 years. 75 (89,3%) received anthracyclines-and taxanes-based CT and 11 (13%). 38 (45,2%) had cytologically proven metastatic axillary nodes at diagnosis. According to intrinsic cancer subtypes, 22 (26%) were classified as HER2 positive, 17 (20,2%) as triple negative (ER, PR, and HER2 -), 6 (7,1%) as luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 &lt; 20% and histological grade 1 or 2)], and 23 (27,4%) as luminal B [estrogen receptor positive and/or progesterone receptor positive and (Ki67 ≥20% or histological grade 3)]. In the univariate analysis, HER2 positivity (p=0,002) and neoadjuvant treatment with trastuzumab (p=0,019) were significantly associated with CAD. In the multivariate analysis only HER2 status maintained statistical significance (p=0,003). Among luminal A, luminal B, and triple negative tumors, complete axillary response after NACT did not significantly predict CAD.
Conclusions: In our cohort of breast cancer patients, HER2 status is an independent predictive factor of CAD after NACT. Clinical trials, probably according to specific breast cancer subtypes, are required to identify patients with initial axillary metastatic involvement who could avoid an axillary dissection after systemic therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-27.
Abstract P2-09-32: Estrogen Receptor-Related Genes Are Important Predictors of Response to Neo-Adjuvant Chemotherapy in Breast Cancer
Authors: Chen Y , Chen C , Xu Q , Ye X , Meng X , Morgin B , Wu J. 
Published: April 2011

Abstract
Background: Clinical data suggest a contribution of estrogen receptor (ER) to chemotherapy response. However, ER status alone is not perfectly predictive, and there is an urgent need for more reliable markers of chemotherapy responsiveness. In this study, we set out to find novel ER-related genes in predicting chemotherapy response by microarrays, hoping to provide more robust multi-variable prediction to chemotherapy. Material and Methods: One hundred and ten patients with stage II-III breast cancer were included, receiving preoperative four cycles of weekly PCb (paclitaxel plus carboplatin) regimen. Pretreatment gene expression profiling was performed with gene microarrays on core biopsy specimens. 55 training cases were used for marker discovery and to identify any ER-related genes that might be associated with response (“training cases”), and the other 55 patients were available as an independent validation set (“validation cases”) to test whether the ER-related genes do predict pCR in protein levels by immunohistochemistry (IHC). Results: In the training cases, the yield of total RNA was insufficient to assay in 16 patients and 8 chips failed in the quality check (QC) process. Therefore, gene expression profile from 31 samples were available for this study. The overall pCR rate in the 86 patients was 19.7% (n=17, 6 cases of pCR in training set and 11 pCR in validation set). In the training set, by Significance Analysis of Microarrays (SAM), 300 probes (231 genes) were identified as differentially expressed between pCR versus non-pCR when fold change &gt; 2. There were 20 differentially expressed genes, setting fold change &gt; 3. Among these 20 genes, TFF1, ESR1, GATA3, TFF3 were found as ER-related. In 55 independent validation cases, univariate analysis indicated that clinical variables and ER-related genes, including ER, PR, GATA3, TFF1 and TFF3 were all significantly associated with pCR (Pearson x2, P&lt;0.001, P=0.013, P&lt;0.001, P&lt;0.001, P&lt;0.001). Multivariate logistic regression model showed that ER (P=0.016) remained significantly associated with complete remission. In spearman analysis, these 5 ER-related genes were significantly correlated with each other (P&lt;0.05). It was found that pCR rate was as high as 80% (4/5) when these 5 factors were all negative. In contrast, these 5 factors were all positive in 7 of 9 PD/SD patients.
Discussion: ER combined with ER-related genes expression status may provide important predictive value of response to neoadjuvant chemotherapy and allows to identify a subgroup of patients who might highly benefit from chemotherapy and who might be resistant to it.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-32.