bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-06-04: Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive markers of response to trastuzumab in patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy + trastuzumab in the REMAGUS02 trial
Authors: Mathieu MC , Goubar A , Sigal B , Bertheau P , Guinebretière JM , André F , Pierga JY , Delaloge S , Giacchetti S , Brain E , Marty M 
Published: August 2014

Abstract
Background: Predicting a benefit from trastuzumab in patients with HER2+ breast cancer remains an important goal. Possible mechanisms of resistance include altered receptor antibody interaction, Akt and MAPK pathways, and loss of p27. The objective of this study was to determine the correlation between pMAPkinase (pMAPK), pAKT, p27, IGF-IR protein expression and the benefit of trastuzumab for patients randomized to chemotherapy (CT) alone and CT with trastuzumab.
Patients and methods: From May 2004 to October 2007, 120 patients with stage II and III HER2+ breast carcinomas were enrolled in a phase II trial of neoadjuvant chemotherapy (CT) with epirubicin-cyclophosphamide (4 courses) followed by docetaxel ± trastuzumab (T) (4 courses). A complete pathological response (pCR) was defined by the absence of residual invasive carcinoma in the breast and axillary lymph nodes. A tissue microarray was constructed from paraffin-embedded tumor samples collected prior to neoadjuvant chemotherapy. Patients' tumours were scored HER2 3+ immunohistochemically (IHC) or 2+ IHC with HER2 amplification by FISH. Immunohistochemical analysis of pMAPK, pAKT, p27 and IGF-IR was performed on tumor tissue microarrays before CT. The H-score (intensity × %) was evaluated. Specimens were classified as exhibiting high or low expression based on a median value as the cut-off point for each marker. A logistic regression model, including the marker and its interaction with treatment, was used to analyse the markers predictive of a treatment effect on the pCR. The independent predictive value was analysed in a multivariate logistic regression adjusting on the lymph node and ER status.
Results: 117/120 (97.5%) patients had sufficient tumor for the analysis. The pCR rate was 19% in the CT arm and 25% in the CT+T arm. The median H-score was: pMAPK = 28, pAKT= 25, p27= 50 and IGF-IR = 15. No significant difference was observed in the pCR rate between the two arms according to pAKT, p27, IGF-IR expression. The pCR rate was higher in CT+T compared to CT alone in patients with high pMAPK expression (OR = 4.7 (0.9–24.2); interaction p = 0.03). No difference was observed in the pCR rate in patients with low pMAPK expression (OR = 0.5 (0.1–1.8).
Conclusions: In HER2-positive breast cancers, pMAPK expression evaluated by IHC was significantly associated with a pathological response in the arm with neoadjuvant trastuzumab. High pMAPK expression could be a predictive marker of response to trastuzumab in a CT +T regimen.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-04.
Abstract P3-06-05: Expression of SPARC in human breast cancer and its predictive value in the GeparTrio neoadjuvant trial.
Authors: Untch M , Prinzler J , Fasching P , Müller BM , Gade S , Meinhold-Heerlein I , Huober J , Karn T , Liedtke C , Loibl S , Müller V , Rack B , Schem C , Darb-Esfahani S , von Minckwitz G , Denkert C 
Published: August 2014

Abstract
Background: Secreted protein acidic and rich in cysteine (SPARC) is an albumin-binding protein and associated with poor prognosis in multiple cancers.
The aim of this analysis was to determine the frequency of SPARC expression among different molecular breast cancer subtypes and to evaluate its predictive value for therapy response after neoadjuvant anthracycline/taxane based chemotherapy (CTX) in participants of the GeparTrio trial.
Methods: We evaluated tumoral SPARC expression by immunohistochemistry on tissue microarrays (TMAs) constructed from formalin-fixed paraffin-embedded (FFPE) pre-treatment core biopsies from 667 patients (pts) of the GeparTrio trial. The details of the GeparTrio study design are described elsewhere (von Minckwitz, JNCI 2008). Cutoffs for SPARC expression were determined using the web-based software Cutoff Finder (http://molpath.charite.de/cutoff/).
Results: SPARC protein expression was measurable by IHC on the TMAs and 176 (26.4 %) of 667 tumors were SPARC positive. SPARC expression was increased in pts with triple-negative breast cancer (TNBC) compared to hormone receptor or HER2 positive subtypes (p = 0.039).
SPARC positivity was associated with an increased pCR rate in the overall population (p &lt; 0.001). SPARC negative tumors had a pCR rate of 15%, which increased to 27% in SPARC positive tumors. Similarly, in TNBC the pCR rate increased from 26% in SPARC negative tumors to 47% in SPARC positive tumors (p = 0.032).
In multivariate logistic regression analysis adjusted for standard clinicopathological factors, SPARC was independently predictive in the overall population (p = 0.010) as well as the subgroups of pts with TNBC (p = 0.036).
Conclusions: SPARC is expressed in all biological breast cancer subtypes with TNBC revealing the highest expression rate. Our data suggest that SPARC expression may provide predictive information for response to neoadjuvant CTX.
As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of nab-Paclitaxel, prospective analysis of SPARC expression is planned in the GeparSepto trial.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-05.
Abstract P3-06-06: Lactate dehydrogenase B in breast cancer contributes to glycolytic phenotype and predicts response to neoadjuvant chemotherapy
Authors: Dennison JB , Molina JR , Mitra S , Gonzalez-Angulo AM , Brown RE , Mills GB 
Published: August 2014

Abstract
Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic heterogeneity is less well understood. This study aimed to identify and evaluate metabolic biomarkers in breast cancers and determine their ability to predict outcomes.
Methods: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes, those with the highest potential for robust high/low classification in a clinical setting. Using a panel of breast cancer cell lines, expression and activity of the highest scoring bimodal metabolism gene, lactate dehydrogenase B (LDHB), was quantified and associated with glycolytic phenotype. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and HCC1937 cell lines with stable lentiviral knockdown of LDHB. mRNA expression of LDHB was evaluated for association with neoadjuvant chemotherapy response within clinical and PAM50-derived subtypes.
Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using four independent patient datasets, LDHB mRNA expression was positively associated with basal subtype and negatively associated with luminal and HER2 subtypes. Furthermore, LDHB predicted basal phenotype independently of hormone-receptor (HR) clinical status (OR = 21.6 for HR-positive/HER2-negative and OR = 18.2 for triple-negative). While LDHB expression could predict basal phenotype, high LDHB expression identified aggressive breast cancer tumors that were primarily but not exclusively basal. Importantly, high LDHB expression predicted pathological complete response to neoadjuvant chemotherapy for both hormone receptor (HR) positive/HER2-negative (OR = 4.0, P = .0002) and triple-negative (OR = 3.0, P = .003) cancers. Consistent with increased response to chemotherapy, LDHB expression in basal cancers within the triple-negative group was associated with the proliferative marker CCNB1 (P &lt; .0001).
Conclusion: mRNA expression of LDHB as a single marker predicted glycolytic phenotype in cell lines and response to neoadjuvant chemotherapy in breast cancers independently of HR status. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for breast cancer patients treated with neoadjuvant chemotherapy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-06.
Abstract P3-06-12: Effect of TOP2A and cMYC gene copy number on outcome in a Phase II trial of adjuvant TC (Docetaxel/Cyclophosphamide) plus trastuzumab (HER TC) in HER2-positive early stage breast cancer
Authors: Jones S , Collea R , Paul D , Sedlacek S , Favret A , Gore I , Lindquist DL , Holmes FA , Allison MAK , Steinberg MS , Stokoe C , Portillo RM , Crockett M , Wang Y , Lina A , Robert NJ , O'Shaughnessy J 
Published: August 2014

Abstract
Introduction: Approximately one-third of HER2+ early stage breast cancer (ESBC) patients have TOP2A-amplified breast cancer, the subpopulation known to benefit from anthracycline use (Press et al, JCO 2011). Data are needed to evaluate whether outcomes in ESBC patients treated with nonanthracycline-based regimens like docetaxel and cyclophosphamide + trastuzumab (HER TC) are affected by TOP2A or cMYC gene copy number.
Methods: This was an open-label, phase II study of HER TC in HER2+ breast cancer patients. Outcome data have been previously reported (Jones et al, SABCS 2011, PD07-03). Tissue was collected to review HER2, cMYC, and TOP2A gene copy number at a central reference laboratory. HER2, cMYC, and TOP2A amplification was defined as FISH ratio &gt;2, and deletion was defined as FISH ratio &lt;1. Every 21 days, patients received T 75mg/m2 IV and C 600mg/m2 IV, plus weekly H 4mg/kg IV (loading dose) and 2mg/kg IV thereafter for a total of 4 cycles. After 4 cycles of TC+H, patients continued on H for 1 year on a 3-week schedule. The primary endpoint was disease-free survival (DFS) at 2 years with continued follow-up for 3 years. Secondary endpoints were overall survival (OS) and safety.
Results: 493 patients with HER2+ ESBC were enrolled. From the 493 patients, 438 (89%) tissue samples were available and analyzed at Caris Diagnostics (Phoenix, AZ) to test for TOP2A, cMYC, and HER2 gene copy number by FISH. HER2 status was confirmed as positive in 87% of samples. Results for TOP2A, cMYC, and HER2 were generated in 438, 436, and 438 samples, respectively. TOP2A was classified as amplified in 43%, normal in 30%, deleted in 27%. cMYC was classified as amplified in 99(23%), normal in 246(56%), and deleted in 91(21%). Three-year DFS and OS in TOP2A and cMYC status as well as ER and Nodal status are depicted in Table 1. Multivariate analyses of age, nodal status, ER status, and gene expression shown below in Table 2 indicate that neither cMYC nor TOP2A status had an effect on outcome. Only nodal and ER status affected outcome.

Conclusion: Outcome (DFS + OS) in a phase II study of a nonanthracycline regimen (TC) coupled with H was unaffected by cMYC or TOP2A gene copy number status. Only ER and nodal status showed an effect in a multivariate analysis.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-12.
Abstract P3-06-17: Detection and monitoring of circulating endothelial cells, circulating tumor cells and disseminated tumor cells during neoadjuvant treatment including an anti-angiogenic agent
Authors: Mathiesen Randi R , Borgen Elin F , Schirmer Cecilie B , Johanssen Ingunn S , Sætersdal Anna B , Wist Erik A , Engebråten Olav 
Published: August 2014

Abstract
Withdrawn by Author
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-17.
Abstract P3-06-22: Mechanisms behind trastuzumab resistance as neoadjuvant therapy in HER2-positive operable breast cancer
Authors: Jinno H , Sato T , Hayashida T , Takahashi M , Hirose S , Kitagawa Y 
Published: August 2014

Abstract
Background: The development of trastuzumab has had a major impact in treatment of breast cancer patients with HER2 overexpression. Despite clinical usefulness, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. Potential mechanisms include aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer.
Patients & methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) for 12 weeks before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. ER and PgR status was assessed using Allred score. For Ki67 labeling index, a total of 400 cells were counted from three consecutive high-power magnifications. PTEN, pIGF-1R and MUC4 expression level was scored semiquantitatively based on staining intensity. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. pCR was defined as no residual invasive carcinoma in the breast.
Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. The overall response rate was 86.5%, including a complete response in 21 patients and a partial response in 11 patients. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 and pIGF1-R status did not affect the pCR rate. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. pCR rate was significantly correlated with PgR negativity (p = 0.004) and higher Ki67 (p = 0.01).
Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-22.
Abstract P3-06-23: Predicting response to neoadjuvant letrozole
Authors: Larionov A , Turnbull A , Sims A , Renshaw L , Kay C , Harrison D , Dixon JM 
Published: August 2014

Abstract
Background: Approximately 75% of older postmenopausal patients with large operable or locally advanced oestrogen receptor positive breast cancer respond to treatment with neoadjuvant letrozole. Prediction of response is required as approximately 25% fail to respond. The aim of this study was to design a response predicting classifier with two data sets, one published previously [1] and secondly a new dataset.
Methods: Patients were treated with Letrozole (Femara, 2.5 mg daily) and tissues were collected before treatment, 2 or 3 weeks on treatment, and between 3 and 5 months on treatment. Response was based on a 3D ultrasound, with response being classified as a 50% reduction in tumour volume at 3 months. To ensure biological relevance of the response groups we also separated patients into Quick Stable Responders (QSR) and Long-Term Non-responders (LNR), as summarised in Table 1.

Illumina HT-12 BeadArrays were used for gene expression profiling, allowing platform-independent cross-validation with our previous study using Affymetrix HGU-133 chips [1]. The probe IDs were re-annotated to Ensemble gene IDs and XPN batch correction has been applied to make the datasets directly comparable. A combination of Rank-Product, SAM and Random Forrest analyses have been used to design several alternative signatures separating extreme response groups, the patients who responded rapidly vs those who did not respond for a long time. One of the best performing signatures included 48 informative features: 24 at baseline, 12 at 2-weeks and 12 changes between 0 and 2 weeks. This signature was validated on the independent previously published test set by classifying extreme responses (quick stable responders vs long term non responders) using Support vector machines (SVM) with different kernel functions.
Results Are summarised in Table 2.

Conclusions  – A new sample series has been collected to study neo-adjuvant endocrine response. It can be used for independent validation of previous results [1] and for design of new platform-independent response predictors.– Multi-gene predictors based upon change in gene expression outperform those from baseline or 14 day measurements alone. The best classifiers include all 3 time points.– A classifier has been derived with a 91% accuracy rate of predicting extreme response group in 21 of 23 patients.
References
[1] Miller 2009 J Clin Oncol 27:1382.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-23.
Abstract P3-06-26: Serum anti-p53 antibody titers predict pathological response to preoperative chemotherapy in women with HER2 positive or triple negative breast cancer.
Authors: Yoshiyama T , Nakamura Y , Igawa A , Saruwatari A , Shigechi T , Ueda N , Kuba S , Ishida M , Nishimura S , Nishiyama K , Ohno S 
Published: August 2014

Abstract
Background: In SABCS 2009, we reported that the high level of serum anti-p53 antibody titers was associated with response to preoperative chemotherapy in cases with primary breast cancer (SABCS 2009). Prognostic meaning of pathological complete response (pCR) after preoperative chemotherapy differs among various subtype, and there is a close relationship between pCR and prognosis in cases with HER2 positive or triple negative disease. The aim of this study is to evaluate the association between the high level of serum anti-p53 antibody titers and pCR in patients with HER2-positive or triple negative breast cancer.
Patients and Methods: In this study, we analyzed 196 women with operable early stage breast cancer (T1-T3, N0-1) treated with preoperative chemotherapy and definitive curative surgery since 2002 to 2011. All of the patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). The serum anti-p53 antibody titers were assessed by ELISA with the anti-p53 EIA Kit II (MESACUP anti-53 Test: MBL) in the pre-treatment serum samples. The test's cut-off value was determined to be 1.3 IU/ml based on reference distribution in healthy control individuals. The association between serum anti-p53 antibody titers and pCR was analyzed.
Results: The subtype of tumors of 196 patients were classified to 86 of ER+/HER2−, 24 of ER+/HER2+, 29 of ER−/HER2+ and 57 of ER−/HER2−. The pCR was achieved 49 of 196 patients (25%). The pCR rate were 7%(6/86), 33%(8/24), 48%(14/29) and 37%(21/57) in the subtype of ER+/HER2−, ER+/HER2+, ER−/HER2+ and ER−/HER2− respectively. The range of serum anti-p53 antibody titers in the serum samples of 196 patients was between 0.40 and 5610 (the median was 0.40 and the average was 85.2). Excluding 86 cases with ER+/HER2−, relationship between serum anti-p53 antibody titers and pCR was evaluated. According to serum anti-p53 antibody titers with the patients of pCR, cut-off value of serum anti-p53 antibody titers was set to be 6 IU/ml. The pCR was observed in nine of 12 cases (75%) with high serum anti-p53 antibody titers, which was significantly higher than those with low titers (35%: 34/98; p = 0.01). Multivariate analysis showed that the only high anti-p53 antibody titer was an independent predictive factor for pCR due to preoperative chemotherapy (p = 0.01).
Conclusion: p53 mutation analysis using serum anti-p53 antibody titers might be a useful predictive test for response to preoperative chemotherapy in patients especially with HER2 positive or triple negative breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-26.
Abstract P3-07-08: Recent trends in the characteristics of patients with distant stage breast cancer in the United States Surveillance, Epidemiology and End Stage Disease (SEER) program
Authors: Li J , Dalvi T , Pawaskar M , Tsai K , Caspard H , Fryzek J 
Published: August 2014

Abstract
Objectives. Even though advances in screening and contemporary diagnostic techniques have led to earlier detection, a proportion of breast cancer patients are still diagnosed with distant stage disease. The objective of this research was to describe the changing demographic and clinical characteristics of patients with distant stage breast cancer.
Methods. We identified women aged 20 years or older who were diagnosed with distant stage primary breast cancer between 1995 and 2009 with non-missing hormone receptor (HR) status in the SEER 18 Registry (1973–2009) database. As staging systems changed across the years of the study, we opted to use the SEER historic stage in our analyses. Trends in demographic and clinical characteristics were evaluated by time period of diagnosis (1995–1999, 2000–2004, 2005–2009) and HR status (HR+ includes ER+/PR+, ER+/PR- and ER−/PR+; HR− includes ER−/PR− only). Statistically significant changes were examined using the Cochran Armitage test.
Results. A total of 30,161 women with distant stage breast cancer were identified. Over the 15 years, the incidence rate (IR) of distant stage disease was stable (10.6 to 10.9 per 100,000 pys), as well as the proportion of HR+ cases (68%).
Age did not vary significantly over time; 55% of the HR+ cases and 45% of the HR- cases were 60 years or older. The proportion of Black and Hispanic patients increased significantly over time (18 to 24% for HR+; 24 to 33% for HR−) -as did the proportion of patients diagnosed with grades I and II cancers (44 to 54% for HR+; and 16 to 20% for HR−). The proportion of ductal histologic diagnoses was stable over time, at 77% among HR+ cases and 93% among HR- cases in 2005–2009. Cancer-directed surgeries (from 63 to 47% for HR+; 72 to 56% for HR−) and radiation therapies (43 to 37% for HR+; 42 to 38% for HR−) became less common over the time. Information on chemotherapy/systemic therapies is unavailable in this dataset.
Conclusions. Although, incidence rate of distant stage breast cancer was stable over a time, there was a higher proportion of diagnosis of grade I/II stage cancer cases potentially due to earlier cancer detections by screening programs. The growing proportion of minorities suggested that screening programs be adjusted to the changing demographics in the United States.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-08.