bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-09-10: Feasibility Assessment of Pharmacogenomic Predictors Developed from Breast Cancer Cell Lines To Predict Breast Cancer Patient Pathological Response in Neoadjuvant Chemotherapy
Authors: Shen K , Rice S , Gingrich D , Wang D , Tian C , Ding Z , Brower S , Ervin P , Huang S , Gabrin M , Song N. 
Published: April 2011

Abstract
Background: Studies of developing pharmacogenomic predictors from cancer cell lines to predict cancer patient clinical response and outcome to chemotherapy have yielded both positive and negative results. The variability in these results may arise from the noise inherent of microarray technology as well as the small sample size of in cell line studies. Therefore, it is greatly needed to evaluate the feasibility of using cell lines to develop pharmacogenomic predictors of patient pathological response. Material and Methods: Thirty breast cancer cell lines were exposed to 10 concentrations of paclitaxel-5-fluorouracil-doxorubicin-cyclophosphamide (TFAC) to measure in vitro chemosensitivity. Two independent and publicly available microarray datasets (Hoeflich and Neve) on these breast cancer cell lines together with the chemosensitivity results were used to identify pharmacogenomic predictors from each dataset. Two independent clinical trials (Hess and Popovici) with publically available data, having 130 and 100 patients respectively, were used as test sets to validate the accuracy of the pharmacogenomic predictors. All patients received TFAC as neoadjuvant therapy and the gene expression profiles of patients were assessed before receiving chemotherapy treatment. The patient's pathological complete response (pCR) was determined after treatment to evaluate the chemotherapy efficacy.
The pharmacogenomic predictors developed from each of the cell line studies were evaluated for their ability to predict patient pCR in each of the clinical trials using the supervised principle component regression method.
Results: The pharmacogenomic predictors identified from the Hoeflich and Neve cell line data (training sets) predicted pCR of the patients in the two clinical trials (test sets) with 64%-68% accuracy, 70%-87% sensitivity, and 60%-67% specificity when 100 genes were selected as pharmacogenomic predictors (Table 1).
Conclusions: The four independent prediction results generated in this study demonstrate the feasibility of using breast cancer cell lines to identify pharmacogenomic predictors of response to chemotherapy treatment for breast cancer patients. Future studies will examine the use of drug responses from primary cultures of patient tumors to develop pharmacogenomic predictors of breast cancer patient responses to chemotherapy treatment.
Table 1. Prediction of breast cancer patients’ pCR by pharmacogenomic predictors derived from breast cancer cell lines.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-10.
Abstract P2-09-12: Phosphoproteomic Pathway Profiling of Breast Cancers for Biomarker and Target Discovery for Personalized Therapy
Authors: Kay C , Mullen P , Langdon SP , Harrison DJ , Faratian D. 
Published: April 2011

Abstract
Introduction: The control and activation of signaling pathways has been shown to influence response to targeted therapy (PTEN and PI3K for trastuzumab, KRAS and MAPK for cetuximab). Single tissue biomarkers (eg HER2-receptor status) are often poor surrogates for the activation state of downstream pathways such as MAPK and PI3K. We have used phosphoproteomic profiling in order to reclassify breast tumors for therapeutic response prediction.
Methods: Eleven cell lines were profiled using phosphoproteome arrays (250 targets) and reclassified using unsupervised clustering. Sensitivity to therapy predicted by pathway activation status was correlated with sensitivity to therapies in vitro measured by the AlamarBlue cell viability assay. Target specificity was assayed using in-cell western blotting. Phosphoprotein clusters were validated in 107 breast tumors by reverse phase protein arrays (RPPA), and the expression of targets validated in independent cohorts of cancers by quantitative immunofluorescence (AQUA) on tissue microarrays.
Results: Phosphoproteomic profiling revealed 3 main clusters of breast tumors with overlap with existing molecular phenotypes (luminal, basal, and mixed) and different profiles of pathway activation (Cluster A: anti-apoptotic, Cluster B: growth factor-dependent, Cluster C: cell cycle-dependent). Good to excellent correlations between pathway activation and in vitro sensitivity to targeted therapies were shown for several pathways and individual molecules within pathways, including components of NFkB, STAT, and cell cycle. These biomarkers were shown to be present in clinical cohorts by RPPA and AQUA, and related to molecular phenotype. Conclusions: Phosphoproteomic profiling can be used to reclassify tumors in order to make a priori predictions about therapeutic targeting. These clusters exist in real clinical specimens and are therefore also promising biomarkers for targeted therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-12.
Abstract P2-09-22: Predictive Significance of the Proportion of ER-or PgR-Positive Tumor Cells in Neoadjuvant Chemotherapy for Operable HER2-Negative Breast Cancer
Authors: Osako T , Nishimura R , Okumura Y , Hayashi M , Arima N. 
Published: April 2011

Abstract
Background
Estrogen receptor (ER) and progesterone receptor (PgR) status are predictive for clinical and pathological response in neoadjuvant chemotherapy for operable breast cancer. However, it remains unclear how the proportion of ER-or PgR-positive staining tumor cells affect responses to neoadjuvant chemotherapy. The purpose of this study was to examine the correlation of the proportion of ER-or PgR-positive staining tumor cells with the clinical and pathological responses to neoadjuvant chemotherapy for operable HER2-negative breast cancer. Patients and Methods
From April 2002 to May 2010, 101 patients received neoadjuvant chemotherapy containing epirubicin and taxane in our clinic. We assessed menopausal status, tumor size, lymph node status, histological grade, ER, PgR, p53 and Ki-67. In this study, we defined the positivity of ER and PgR as more than or equal to 1% of the positive staining tumor cells according to ASCO/CAP announcement in April 2010. Furthermore, patients with ER-positive tumor were divided into two groups at 30% of ER positive staining tumor cells. Results
A clinical response was seen in 82% of all patients and a pathological complete response (pCR) was seen in 17%. Of the 101 patients, 60 (59%) had ER-positive tumors and 38 (63%) of the patients had tumors with more than 90% of ER-positive staining cells. Also, 52 (51%) had PgR-positive tumors. Fourteen (34%) of the 41 patients with ER-negative tumors achieved a pCR and 15 (31%) of the 49 patients with PgR-negative tumors achieved a pCR. Patients with more than 30% of ER-or more than 1% of PgR-positive staining tumor cells did not achieve a pCR. There was no significant correlation of pCR with menopausal status, tumor size, grade and Ki-67. In univariate analysis, a pCR was associated with ER status (p=0.0001), PgR status (p=0.0001), and chemotherapy regimens (p=0.014). Multivariate analysis revealed that ER status was a significant factor for pCR, and patients with ER-negative tumors were 20.1 times more likely to achieve a pCR than those with more than or equal to 30% tumors staining tumor cells (p=0.005; 95% confidential interval, 2.5-16.5).
Conclusion
We demonstrated a predictive significance of the proportion of ER-or PgR-positive tumor cells in neoadjuvant chemotherapy for operable HER2- negative breast cancer. ER-negativity (&lt;1%) is significantly predictive to achieve a pCR in multivariate analysis. Conversely, it seems very possible that patients with more than 30% ER-or more than 1% PgR-positive staining tumor cells do not achieve a pCR. It is important to take the proportion of ER-and PgR-positive staining tumor cells into consideration in the treatment of breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-22.
Abstract P2-09-34: ERK Phosphorylation in Fibroblasts within Breast Cancer Stroma Is Associated with an Improved Tamoxifen Response
Authors: Busch S , Ryden L , Stål O , Jirströ K , Landberg G. 
Published: April 2011

Abstract
Background. Extra-cellular signal-regulated kinase (ERK) 1/2 is an integral part of the mitogen-activated protein kinase (MAPK) pathway, transmitting signals involved in cell proliferation and cell death upon binding of extracellular growth factors to their receptors. Whereas its role in tumour cells has been linked to key events in cell transformation, its role in tumour-associated fibroblasts, a component of the tumour stroma, is largely unknown.
Material and methods. Tissue microarrays (TMAs) of two cohorts including invasive breast cancer patients were stained for ERK phosphorylation level (pERK) and SMA-alpha expression (SMAa) which were scored and analysed in regard to clinico-pathological, prognostic and molecular markers and recurrence-free survival.
Results. In both clinical materials we show a significant correlation between stromal ERK phosphorylation and the marker for activated fibroblasts SMAa. SMAa expression was not linked to treatment-predictive information but instead had prognostic qualities (P=0.034, multivariate Cox regression). By analysing the unique randomised tamoxifen trial including patients receiving no adjuvant treatment we show for the first time that ERK phosphorylation in cancer-associated fibroblasts (CAF) was associated with an improved outcome upon tamoxifen treatment. In contrast, patients having ERα-positive tumours but lacking ERK phosphorylation in the stroma did not respond to tamoxifen treatment (P=0.015, multivariate interaction analyses).
Discussion. This suggests that only a subpopulation of activated fibroblasts, defined by phosphorylation of ERK, is linked to a response to tamoxifen treatment illustrating the importance of the stroma for monitoring and potentially mediating treatment effects in premenopausal breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-34.
Abstract P2-09-36: Role of ABCB1 Polymorphisms as Predictive Markers in Patients with HER-2 FISH Positive Metastatic Breast Cancer Who Were Treated with Taxane Plus Trastuzumab First Line Chemotherapy
Authors: Kim J-W , Im S-A , Kim JH , Ham HS , Han H-S , Kim J-S , Kim T-M , Han S-W , Oh D-Y , Lee S-H , Kim D-W , Cho N , Moon WK , Kim T-Y , Park IA , Heo DS , Bang Y-J. 
Published: April 2011

Abstract
Background: ABCB1 polymorphisms could predict treatment results of taxane therapy in several malignancies. FCGR2A and FCGR3A polymorphisms were associated with clinical outcomes in several diseases after treatment with monoclonal antibody drugs which had antibody-dependent cell-mediated cytotoxicity activity. These polymorphisms could be possible predictive markers after taxane plus trastuzumab (TH) chemotherapy in patients with HER-2-positive metastatic breast cancer (MBC).
Methods: Fifty-seven patients with HER-2 FISH positive MBC who received TH chemotherapy as the 1st-line treatment were enrolled. We analyzed 5 polymorphisms using DNA from peripheral blood mononuclear cells: ABCB1 1236C&gt;T (rs1128503), ABCB1 2677G&gt;T/A (rs2032582), ABCB1 3435C&gt;T (rs1045642), FCGR2A 131H/R (rs1801274), and FCGR3A 158V/F (rs396991), then correlated them to treatment results of patients.
Results: Among 57 patients, 22 patients (38.6%) received weekly paclitaxel plus trastuzumab, 26 patients (45.6%) tri-weekly paclitaxel plus trastuzumab, and 9 patients (15.8%) tri-weekly docetaxel plus trastuzumab. After a median follow-up of 30.6 (range, 0.6-75.9) months, median progression-free survival (PFS) was 15.1 (95% confidence interval (CI), 10.3-19.8) months. ABCB1 2677T allele carriers had longer PFS than the others (42.1 (95% CI, 12.7-71.4) months vs. 13.0 (95% CI, 10.6-15.4) months; p=0.037) along with a tendency toward higher response rate (RR) (86.4% vs. 76.0%; p=0.470) and longer overall survival (OS) (54.7 (95% CI, 43.0-66.4) months vs. 38.9 (95% CI, 18.1-59.7) months; p=0.057). In addition, ABCB1 3435CC genotype carriers had shorter PFS than the others (13.0 (95% CI, 10.8-15.2) months vs. 19.1 (95% CI, 0.0-38.5) months; p=0.039) along with a tendency toward lower RR (78.6% vs. 100%; p=0.567) and shorter OS (38.9 (95% CI, 19.7-58.1) months vs. 54.7 (95% CI, 43.0-66.4) months; p=0.093). ABCB1 1236C&gt;T, FCGR2A 131H/R, and FCGR3A 158V/F were not significantly associated with RR, PFS, and OS. None of these polymorphisms were associated with any grades of hematologic or cardiac toxicities.
Conclusions: Our results support that ABCB1 2677G&gt;T/A and 3435C&gt;T may have predictive roles after the 1st-line TH chemotherapy in patients with HER-2-positive MBC. In contrast, ABCB1 1236C&gt;T, FCGR2A 131H/R, and FCGR3A 158V/F could not predict response after TH treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-36.
Abstract P2-09-39: Multi-Gene Predictors Developed from Breast Cancer Cell Lines To Predict Response to Chemotherapy: A Validation Study on US Oncology Study 02-103
Authors: Shen K , Pusztai L , Qi Y , Symmans WF , Song N , Rice SD , Gabrin MJ , O'Shaughnessy JA , Holmes FA. 
Published: April 2011

Abstract
PURPOSE: Multi-gene predictors (MGPs) of response to multidrug chemotherapy regimens were developed using an in vitro chemoresponse assay in which cell lines were exposed to chemotherapy. The goal of this study was to assess the predictive value of these MGPs using clinical breast cancer patient gene expression data from a clinical trial. METHOD: US Oncology 02-103 was a phase II trial in which women with stage II/III breast cancer were treated with neoadjuvant chemotherapy consisting of four cycles of fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX). Most HER-2 positive patients also received trastuzumab. MGPs of FEC, TX and TFEC (docetaxel/fluorouracil/epirubicin/cyclophosphamide) sensitivity were developed using in vitro assay results from breast cancer cell lines exposed to these drug combinations and publicly-available gene expression data for the same cell lines. MGPs were not developed for trastuzumab treatment. Area under the receiver-operator curve (AUC) was used to evaluate the performance of the three MGPs’ to predict patient pathologic complete response (pCR). Patients who did or did not receive trastuzumab were evaluated separately. Validation was performed blindly and the predictors were applied without knowledge of patient clinical outcome. RESULTS: Eighty-six patients had genomic data available and were included in this analysis. The predictive performance of the FEC, TX and TFEC MGPs were AUCs of 0.72, 0.69, and 0.73, respectively, in the patients who received FEC-TX chemotherapy without trastuzumab (n=61). Within this group, higher AUCs were observed in ER-negative patients compared to ER-positive patients (0.69, 0.72, 0.74 vs. 0.64, 0.54, 0.62, respectively). The prediction accuracies were low (AUCs = 0.43, 0.56 and 0.43) for patients who received trastuzumab together with chemotherapy (n=25) as expected, indicating that the MGPs may have the potential to be regimen-specific.
CONCLUSION: Cell line-derived MGPs of multidrug chemotherapy regimens showed promising performance in this blinded validation study, particularly among patients with ER-negative breast cancers. Further clinical data are needed to confirm this finding.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-39.
Abstract P2-10-01: The Accuracy of BRCA1/2 Mutation Prediction Models in Different Ethnicity and Gender: Experience in a Chinese Cohort
Authors: Kwong A , Wong CHN , Suen DTK , Choi CLY , Wong CLP , Law FFB , Kurian A , Ma ESK , West DW , Ford JM. 
Published: April 2011

Abstract
Background: Risk models (BRCAPRO, Myriad, Couch and Shattuck-Eidens, BOADICEA) are well established in Caucasian and African American cohorts to estimate the probability of BRCA1/2 mutation. Few studies have suggested its performance limitation in Asian cohorts. Most studies did not account for gender specific prediction. The aim of the study is to evaluate the performance of these models in a Chinese cohort who have breast/ovarian cancer at a pre-genetic test setting. Methods: Four risk assessment models, Boadicea, BRCAPRO, Myriad, Couch and Shattuck-Eidens, were used to perform risk calculations to 217 non-BRCA carriers (198 females and 19 males) and 32 BRCA carriers (28 females and 4 males. Sensitivity, specificity and area under the receiver operator characteristic (ROC) curve were calculated for each model to evaluate for calibration, discrimination and accuracy in BRCA mutation prediction stratified by gender.
Results: The mean in prediction score in all models were statistically significantly higher in female BRCA mutation carriers. However, there were no statistically difference in mean prediction score between BRCA carriers and non-carriers in all models for male patients. BRCAPRO slightly over-estimated the total numbers of BRCA1 and BRCA2 female carriers (13 vs. 11 and 20 vs.17), but underestimated the number of BRCA2 male carriers (2.8 vs. 4). While Myriad underestimated both the total numbers of BRCA1/2 male (3.1 vs. 4) and female (25.6 vs. 28) carriers. Boadicea did the closest estimation for both male (3.2 vs. 4) and female (1.5 vs. 11 for BRCA1 and 16.3 vs. 17 in BRCA2). BRCAPRO showed the greatest ROC area for BRCA1 (93%), BRCA2 (73%) and BRCA1/2 (79%) combination mutation prediction and highest sensitivity at conventional thresholds of 10% and 20% in female patients (71.4% vs.60.7%). Boadicea had the greatest ROC area for BRCA2 and BRCA1/2 combination mutation prediction and the same sensitivity at conventional thresholds of 10% and 20% in male patients (92% vs. 93%).
Conclusion: All 4 models could perform reasonably well in female patients, but not in male patients. Boadicea has the best performance in male and female Chinese cohort overall. Whereas when comparing females alone, BRCAPRO is most accurate.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-10-01.
Abstract P2-11-02: Mapping Mutations: Importance of Family Geographic Origin in Portuguese High-Risk Breast/Ovarian Cancer Families for BRCA Mutation Screening
Authors: Fragoso S , Machado P , Santos S , Rodrigues P , Parreira J , Bento S , Luís A , Vaz F. 
Published: April 2011

Abstract
Background: Hereditary breast/ovarian cancer is mainly related with BRCA1/2 mutations. The complete screening of both genes is long and expensive due to their large number of exons and the inexistence of hotspots. Besides our most frequent BRCA mutation, c.156_157insAlu in BRCA2, the Portuguese population has many other mutations in these genes, described over the years. Aim: to evaluate the importance of screening specific mutations, found in BRCA positive families, in other probands with the same geographic origin. Patients and methods: 407 high risk breast/ovarian cancer patients were screened for c.156_157insAlu in BRCA2 (the Portuguese founder mutation), BRCA1/2 point mutations and large rearrangements. All probands were questioned about their family origin. Mutations detected in families were studied in new probands with the same geographic origin. Results: we were able to draw a map with the geographic origin of our 87 BRCA positive families. Most of our BRCA families have origin in the centre of Portugal. While searching probands with the same geographic origin as others previously detected, we found three additional mutations without screening the whole genes: 1 family from Madeira island; 1 family from the south (Algarve) and 1 non-affected individual, without previous family testing, that was positive for c.156_157insAlu in BRCA2 (her family had origin in an area of high prevalence of this mutation). Our maps also allowed the linking of several families with the same mutation and family origin, but apparently unrelated. Conclusion: Mapping geographic origin of BRCA1/2 mutations may help in the quick identification of new BRCA1/2 carriers and, in some cases, reduce the screening time. Most importantly it permits the linking of apparently unrelated families. This link permits a more accurate estimation of BRCA1/2 positive families and a better understanding of all at-risk family members.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-11-02.
Abstract P2-12-02: How Common Is Sexual Dysfunction among Women with Early Stage Breast Cancer?
Authors: Dent SF , Frechette DAM , Verma S , Clemons MJ , Wheatley-Price PF , Gertler SZ , Song X , Asmis TR , Graham NA , Paquet L. 
Published: April 2011

Abstract
Background: Despite the high prevalence of sexual problems (50—90%) among women with early stage breast cancer (EBC), relatively little is known about the prevalence of clinically significant post-systemic treatment sexual dysfunction (SD) and its impact on quality of life (QOL). According to the American Psychiatric Association (APA), SD consists of sexual problems causing marked personal distress. While 40% of healthy US women report sexual problems, only 12% experience SD. No study has applied the APA criterion to document the prevalence of SD in women with EBC who have completed systemic therapy. The goal of this study is to address this gap and to examine some correlates (anxious predispositions and menopausal symptoms) of SD and the impact of SD on QOL. Methods: Post-menopausal women receiving cancer therapy for EBC or early colon cancer were approached for this study. Sexual problems were evaluated with the Female Sexual Function Index while sexual distress was assessed with the Female Sexual Distress Scale. QOL was measured with FACT-B, using its endocrine symptoms subscale (ES) to assess menopausal symptoms. Spielberger State-Trait Anxiety Inventory measured anxious predispositions. Participants completed questionnaires upon completion of adjuvant chemotherapy but prior to initiation of hormonal therapy (estrogen sensitive EBC). SD was assessed using the APA classification. Results: Between January 2009 and May 1 2010, 70 EBC patients entered this study. The proportion of women (mean age 61) reporting 1 or more sexual problems was high (93%) and included problems with 1) frequency (66%) and level (65%) of sexual desire, 2) frequency (66%), level (52%) and satisfaction (43%) of arousal, 3) frequency (21%) of vaginal dryness and difficulty becoming lubricated (47%) during sexual activity, 4) satisfaction with their sexual life (30%) and 5) pain during intercourse (18%). However, the APA criterion identified only 30% of patients as having SD. Multiple logistic regression showed that anxiety predispositions and menopausal symptoms predicted SD (p&lt; .01). Women classified as having SD had higher anxiety scores (No SD=34 SD=41, p&lt;.05) as well as higher levels of menopausal symptoms (i.e, lower ES scores; No SD= 62 SD=54, p&lt;.01). QOL was negatively impacted by SD (r=-0.42, p&lt;.01). Discussion: Despite the fact that an overwhelming majority of patients had sexual difficulties, the APA distress criterion identified far fewer patients (30 %) with SD. Nevertheless, we found a high prevalence rate of SD, which was 2.5 times higher (%2 &lt; .01) than that reported in women without a cancer diagnosis. Women with anxious predispositions and high menopausal symptoms may be at risk for SD and may benefit from early interventions to prevent SD.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-12-02.