bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Methods for Detection of Fulvestrant-Induced Changes in Breast Tumor Estrogen and Progesterone Receptor Expression in a Neoadjuvant Trial (NEWEST).
Authors: Kuter I. , Anderson E. , Emeribe U. , Finlay P. , Nicholson R. , Gee J. 
Published: December 2010

Abstract
Background: Fulvestrant downregulates breast tumor estrogen and progesterone receptor (ER and PgR) levels in a dose-dependent manner. Using an Automated Cellular Imaging System (ACIS), NEWEST (NCT00093002) reported that 4-wks' treatment with fulvestrant high-dose (HD, 500mg/month+500mg on Day 14 of Month 1) significantly reduced ER levels in primary breast tumors v approved-dose (AD, 250mg/month). However, no significant difference was detected between the two doses on PgR levels. To allow comparison with previous studies, a non-automated H-score assessment was performed and compared with ACIS.Methods: ER and PgR H-scores were derived by manual assessment of % tumor cells in each of 5 staining categories (negative, very weak, weak, moderate, strong) in the same sections scored by ACIS. This microscopic assessment was performed by 2 experienced observers blind to ACIS and clinical data. Mean % changes in H-scores were then calculated (table).Results: Both scoring methods showed a greater effect for fulvestrant HD v AD on ER expression at Wk 4, but H-score provided better dose discrimination. ACIS showed no difference between fulvestrant HD v AD on PgR expression at Wk 4, however, a significantly greater reduction in PgR expression was detected with fulvestrant HD using H-score.Wk 4Mean % change from baseline ACISH-score HDADHDADER-25.0%-13.5%-50.3%-13.7% n=60(n=63)(n=58)(n=60) p=0.0002 p&lt;0.0001 PgR-22.7%-17.6%-80.5%-46.3% (n=43)(n=45)(n=31)(n=34) NS p=0.0018 Baseline mean H-score for HD and AD: 151.6 and 157.7 for ER; 103.8 and 122.9 for PgR.Conclusion: The choice of scoring method for determining ER and PgR expression in pharmacodynamic studies such as NEWEST is critical. Compared with H-scores, ACIS has a narrower dynamic range and reduced ability to discriminate fulvestrant HD v AD, particularly on PgR expression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1087.
A Pilot Trial of Pre-Operative (Neoadjuvant) Letrozole in Combination with Bevacizumab in Post-Menopausal Women with Newly Diagnosed Estrogen and/or Progesterone Receptor Positive Breast Cancer.
Authors: Forero A. , Saleh M. , Galleshaw J. , Jones C. , Shah J. , Percent I. , Nabell L. , Carpenter J. , Falkson C. , Krontiras H. , Urist M. , Bland K. , De Los Santos J. , Meredith R. , Caterinicchia V. , Bernreuter W. , O'Malley J. , Li Y. , LoBuglio A. 
Published: December 2010

Abstract
Purpose Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods Patients were treated with a neo-adjuvant regimen of letrozole, 2.5mg/day (P.O.) and bevacizumab 15mg/kg Q3 weeks (I.V.) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at 3 week intervals and tumor assessment (physical exam and tumor ultrasound) at 6 week intervals. PET scans were carried out prior to therapy and 6 weeks after initiation of therapy. Surgery was done 4 weeks after the last dose of bevacizumab. Results Twenty five evaluable patients were treated. The regimen was well tolerated except for 2 patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The 4 patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. 8/25 patients (32%) attained stage 0 or 1 status. PET scan response at 6 weeks correlated with clinical CR and breast pathologic CR at 24 weeks (p &lt; 0.0036). Conclusion Combination neo-adjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1088.
Pilot Neoadjuvant Trial with Combination of Lapatinib and Nab-Paclitaxel in HER2+ Breast Cancer.
Authors: Kaklamani V. , Uthe R. , Khan S. , Hansen N. , Bethke K. , Jeruss J. , Cianfrocca M. , Von Roenn J. , Rosen S. , Gradishar W. 
Published: December 2010

Abstract
Background: Lapatinib, a dual kinase inhibitor against EGFR and HER2, has activity in metastatic HER2+ breast cancer. Nab-paclitaxel has been found to be one of the most active agents in metastatic breast cancer. Its combination has not been studied in the neoadjuvant setting. We have conducted a pilot neoadjuvant trial in HER2+ patients (pts) combining lapatinib with nab-paclitaxel.Methods: Females with newly diagnosed breast cancer (stage I-III) received four cycles of lapatinib 1000 mg po/day and nab-paclitaxel 260mg /m2 IV every three weeks. Postoperative therapy was at the discretion of the investigator. The accrual goal of 30 pts has been met. The primary endpoint was clinical response rate (CRR) with secondary endpoints including pathologic complete response (pCR), toxicity, and proliferation, apoptosis and angiogenesis markers.Results: A total of 28 pts have completed all therapy to date. The most common toxicities were rash, neuropathy, fatigue and myalgias. Most toxicities were grade 1/2 although one pt developed grade 3 rash and five pts grade 3 diarrhea. Nab-paclitaxel was dose reduced in 8 and lapatinib in 10 of 104 cycles. No cardiac toxicity was observed. Response data is available on 25 pts. CRR was 88% with four complete clinical responses and 18 patients with partial clinical response. Three patients had stable disease. Four patients achieved pCR.Summary of efficacy and toxicityResponse Non-hematologic ToxicityGrade 1/2Grade 3/4Hematologic toxicity Overall response22 (88%)Nausea7 (25%)1 (3.6%)Anemia9 (32.1%)Complete response4 (16%)Rash19 (67.8%)1 (3.6%) Partial response18 (72%)Fatigue17 (60.7%)2 (7.2%) Stable disease3 (12%)Neuropathy14 (50%)0 pCR4 (19.0%)Arthralgias/17 (60.7%)1 (3.6%) Diarrhea15 (53.6%)5 (17.9%) Conclusions: The combination of lapatinib and nab-paclitaxel is very active as first-line treatment in HER2+ breast cancer. Toxicities, including rash and diarrhea were observed and medically managed. Patients did not receive prophylactic medications for rash or diarrhea Updated clinical data on all 30 patients as well as correlative markers will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1091.
Five Years of Exemestane as Initial Therapy Compared to 5 Years of Tamoxifen Followed by Exemestane: The TEAM Trial, a Prospective, Randomized, Phase III Trial in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer.
Authors: Rea D. , Hasenburg A. , Seynaeve C. , Jones S. , Vannetzel J. , Paridaens R. , Markopoulos C. , Hozumi Y. , Putter H. , Hille E. , Asmar L. , Urbanski R. , van de Velde C. , Bartlett J. , Smeets J. , Kieback D. 
Published: December 2010

Abstract
Background: Exemestane (E) is a steroidal aromatase inhibitor (AI) with an established role in early breast cancer after 2–3 years of tamoxifen (T). Additionally, AIs have shown superiority to T as initial adjuvant therapy. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) study has been prospectively designed to compare the role of E as initial adjuvant therapy with a sequential approach of T followed by E (T→E).Methods: Postmenopausal patients with hormone receptor–positive early breast cancer were randomized to open-label E 25 mg/d or T 20 mg/d. All patients completed surgery and chemotherapy, if indicated. Data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with the primary objective being a comparison of disease-free survival (DFS) with T vs E. In 2004, TEAM was modified in response to new data; all those initially receiving T were switched to E after 2.5–3 years. An additional 2500 patients were recruited and randomized at diagnosis to E or T→E for 5 years. The modified study design includes 2 coprimary endpoints: (1) DFS of T vs E that was previously reported at 2.75 years median follow-up (Jones S et al, abstract #15 presented at SABCS 2008); and (2) DFS at 5 years of E vs T→E that will be the focus of results presented here.Results: Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy. In September 2009, median follow-up will be 5.5 years and the protocol-specified 1285 overall DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) will have occurred, allowing for analysis of the second coprimary endpoint. We will present a detailed analysis of the 5-year results from theTEAM trial, the only prospectively powered randomized trial to compare 5 years of an initial AI vs T→AI, 2 commonly received adjuvant therapies for women with hormone receptor–positive early breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 11.
A Phase II Trial of Capecitabine and Docetaxel Followed by 5-FU/Epirubicin/Cyclophosphamide (FEC) as Preoperative Treatment in Women with Stage II/III Breast Cancer.
Authors: Jinno H. , Takahashi M. , Hayashida T. , Sakata M. , Mukai M. , Kitagawa Y. 
Published: December 2010

Abstract
Backgound: capecitabine (X) and docetaxel (T) have demonstrated synergistic effect in preclinical models and survival benefit in metastatic breast cancer. The sequential combination of anthracycline and taxane is a standard of care as preoperative setting, as well as adjuvant setting. This study's purpose was to determine the efficacy of X and T followed by 5-FU/epirubicin/cyclophosphamide (FEC) in the preoperative setting.Patients and Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine 1650 mg/m2 on days 1-14 and docetaxel 60 mg/m2 on day 8 every 3 weeks), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). Primary endpoints were the pathological complete response (pCR) rate and adverse drug reactions. pCR was defined as no microscopic evidence of residual viable tumor cells, invasive or noninvasive, in all resected specimens of the breast. Secondary endpoints were the clinical response rate, the breast conservation rate, and predictors for pCR.Results: From February 2005 to October 2008, 72 patients were enrolled and 71 patients were assessable for clinical and pathologic responses. The median age was 51 years (range, 27-69 years). The median tumor size was 3.5 cm (range, 2-8.3 cm). Forty-six (64.8%) patients were clinically node-positive. Overall, 50 (50.1%) patients had hormonal receptor (HR)-positive tumors, and 21 (29.6%) had HR-negative tumors. The overall response rate was 91.5%, including a complete response in 29 patients and a partial response in 36 patients. No patients showed clinical progression of disease. The pCR rate was 14.1% (10/71). Fifty-six patients (78.9%) underwent breast-conserving surgery. The breast-conserving rate in patients whose tumor size was 3 cm or smaller was 92.6%, and 69.0% of patients whose tumor size was larger than 3 cm underwent breast-conserving surgery. Grade 3/4 neutropenia was observed in 32.4% of patients, and febrile neutropenia was observed in 5.6% of patients. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 11.3% of patients. The median relative dose intensities of FEC, T, and X were 0.982, 0.968, and 0.933, respectively. HR status and Ki67 expression were significantly correlated with pCR.Conclusions: These data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective preoperative treatment for stage II/III breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1101.
Circulating Tumor Cells and FDG-PET/CT for the Therapeutic Monitoring of Bone Metastases from Breast Cancer.
Authors: De Giorgi U. , De Giorgi U. , Mego M. , Rohren E. , Valero V. , Handy B. , Jackson S. , Reuben J. , Macapinlac H. , Cristofanilli M. , Ueno N. 
Published: December 2010

Abstract
Background: Circulating tumor cells (CTCs) and [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) are two promising new tools for monitoring therapy in patients with metastatic breast cancer. The two modalities showed high sensitivity in detection of bone relapse/progression from breast cancer (De Giorgi U et al. Ann Oncol 2009). In this study, we sought to evaluate the prognostic significance of two different modalities represented by the detection of CTC and FDG-PET/CT in patients with bone metastases from breast cancer treated with standard therapies. Our objective was to compare the two modalities to identify which technology could be more sensitive in prospectively monitoring such patients.Patients and Methods: This is a retrospective study of 54 patients with bone metastases from breast cancer without visceral metastases treated at The University of Texas M. D. Anderson Cancer Center from September 2004 to May 2008. CTC were detected and enumerated using the CellSearch system (Veridex LLC, Rariten NJ, USA). Patients were categorized according to first follow-up CTC counts as having a favorable (&lt; 5 CTC/7.5 mL of blood) or unfavorable (≥ 5 CTC) outcome. Reassessment of disease status by CTC count and FDG-PET/CT was performed approximately 2-3 months after initiation of the new treatment, depending on treatment type and schedule. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: In 54 evaluable patients, the median overall survival time was 17 months (range, 3 to &gt;36). Follow-up CTC levels and FDG-PET/CT response predicted both PFS (p = 0.02 and p = 0.0001, respectively) and OS (p = 0.01 and p = 0.02, respectively), while baseline CTC predicted neither PFS (p = 0.8) nor OS (p = 0.76). In patients with either CTC or FDG-PET/CT response PFS has been 13 months, while in patients with discordant CTC and FDG-PET/CT response PFS has been 6 months and in patients with neither CTC nor FDG-PET/CT response PFS has been 5 months (p = &lt;0.00002). In patients with either CTC or FDG-PET/CT response, OS has not been reached (&gt;31 months); in patients with discordant CTC and FDG-PET/CT response, OS has been 24 months; and in patients with neither CTC nor FDG-PET/CT response, OS has been 18 months (p = 0.02).Conclusions: CTC and FDG-PET/CT are useful tools for therapeutic monitoring of bone metastases from breast cancer. Prospective studies in this specific clinical context are needed to assess the critical roles that CTC and FDG-PET/CT individually as well as collectively play in the prognostic and therapeutic monitoring of bone metastases from breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1109.
A Genomic-Profile Derived Summary Measure of Chromosomal Breakpoints Predicts Response to Treatment with the DNA-Damaging Agent Cisplatin.
Authors: Juul N. , Wang Y. , Kim J. , Eklund A. , Li Q. , Carlton V. , Gerlinger M. , Swanton C. , Garber J. , Silver D. , Faham M. , Richardson A. , Szallasi Z. , Szallasi Z. , Wang Z. 
Published: December 2010

Abstract
Cisplatin-based chemotherapy promotes DNA inter- and intra-strand cross-links and is effective treatment in multiple cancer types, yet it is rarely used for first-line therapy of breast cancer. Cisplatin is an effective cytotoxic in BRCA1 mutant cancer cell lines and in breast and ovarian cancers with BRCA1 mutations, prompting speculation that defective DNA double-strand break repair is associated with cisplatin sensitivity. Furthermore, tumors with BRCA1 mutation are presumed to be defective in various aspects of DNA repair and also display increased levels of chromosomal instability. Thus, we hypothesized that the total number of chromosomal breakpoints in a specific tumor may reflect defective DNA repair and/or chromosomal instability, and may therefore be used as a predictor of cisplatin sensitivity. Supporting this relationship, we identified a correlation (r = 0.8, P = 0.08) between the total number of chromosomal breakpoints, estimated by the number of genomic regions showing allelic imbalance, and cisplatin sensitivity in five triple negative breast cancer cell lines. To validate this relationship in a clinical setting we compared the total number of chromosomal breakpoints to therapy response in a cisplatin treated breast cancer cohort. A total of 28 women with stage II or III ER-/PR-/HER2- breast cancer were treated with cisplatin in the neo-adjuvant setting followed by surgery and standard adjuvant chemotherapy. A core biopsy was obtained before treatment commenced, tumor cells were enriched by needle microdissection, and DNA was extracted for genotyping. As only limited amounts of DNA were available, we used a Molecular Inversion Probe assay (in collaboration with Affymetrix), which allowed us to genotype 42,000 SNPs with only 40 ng of starting DNA. We then estimated the total number of putative genomic breakpoints in 21 samples containing at least 75% tumor cells. We compared this summary genomic measure to the response rate as quantitated by the Miller-Payne score determined on the pathological specimen obtained at surgery. This genomic measure showed a remarkably accurate separation of patients by degree of response, correctly classifying 20 out of 21 patients (P &lt; 0.001).These results suggest that the total number of DNA breakpoints may be an accurate biomarker of breast cancers which may be sensitive to cisplatin treatment. The molecular explanations for these findings await further work.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 111.
Inhibition of Calcitonin Gene-Related Peptide and Insulin-Like Growth Factor: A Potential New Therapeutic Strategy To Reduce Bone Pain in Bone Metastases of Breast Cancer.
Authors: Sakurai T. , Sakurai T. , Sakurai T. , Umemura T. , Jinta E. , Suzuma T. , Williams P. , Yoshimura G. , Wakabayashi H. , Sakurai T. , Yoneda T. , Yoneda T. 
Published: December 2010

Abstract
Bone pain caused by bone metastases is one of the most common complications in patients with breast cancer. However, the precise molecular mechanism of bone pain is unknown. We have shown that the acid released upon bone resorption by osteoclasts and the transient receptor potential vanilloid receptor (TRPV1), an acid-sensing receptor on the algetic nerves terminating at the bone, are involved in the mechanism underlying this bone pain. In this study, we investigated the relationships among TRPV1, bone-derived insulin-like growth factor-1 (IGF-1) which is released from bone due to increased bone resorption during the progression of bone metastases, and neuropeptide calcitonin gene-related peptide (CGRP) and examined whether cancer-induced bone pain can be decreased by the inhibition of IGF-1 and CGRP. To study this in vitro, we established organ cultures of mouse dorsal root ganglions (DRGs), which are the primary sensory neurons innervating bone. Culture supernatants harvested from the mouse neonatal calvariae, which had abundant growth factor in bone, showed elevated TRPV1 and CGRP mRNA expressions in mouse DRGs. These up-regulated mRNA expressions were inhibited by the administration of a TRPV1 inhibitor (I-RTX); AG1024, a specific inhibitor of IGF receptor tyrosine kinase; or zoledronate. Taken together, these results suggest that CGRP and bone-derived IGF-1 may play a role in the induction of bone pain. To approach the role of CGRP and bone-derived IGF-1 in vivo, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. RT-PCR showed elevated mRNA expression of TRPV1 and CGRP in the ipsi-lateral tumor-bearing DRGs. The administration of a CGRP inhibitor (CGRP 8-37) in a continuous manner using an ALZET osmotic pump implanted under the mouse skin; the intraperitoneal administration of AG1024; and the administration of alendronate significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of CGRP was decreased by CGRP 8-37, and mRNA expression of TRVP1 and CGRP was also decreased by AG1024 in the ipsi-lateral DRGs. Neither of these drugs showed a direct effect on the growth of the tumor in this study. In conclusion, our results suggest that TRPV1, CGRP, and the bone-derived IGF-1 are strongly related and might play a role in breast cancer-induced bone pain. The inhibition of the CGRP and bone-derived IGF-1 could be a potential therapeutic strategy to reduce bone pain; although further investigations are required in this direction.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1110.