bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-14-02: Sequential Versus Upfront Intensified Neoadjuvant Chemotherapy in Patients with Large Resectable or Locally Advanced Breast Cancer (INTENS), Toxicity Results from a Phase III Study of the Dutch Breast Cancer Trialists' Group (BOOG).
Authors: Vriens BE , Van de Vijver KK , Boetes C , van Gastel SM , Wals J , Smilde TJ , van Warmerdam LJ , van Laarhoven HW , van Spronsen DJ , Borm GF , Tjan-Heijnen VC 
Published: June 2012

Abstract
Background Taxanes have an established role as (neo-)adjuvant treatment of breast cancer. In the present study, we compared 4 AC - 4 T with 6 cycles of TAC in the neo-adjuvant setting (A=adriamycine, C=cyclophosphamide, T=docetaxel). Previously, we reported that AC-T resulted in a trend for improved outcome (odds ratio pCR of the breast 1.61; 95% CI 0.79−3.33). Now we report the safety data.
Methods Women presenting with breast cancer, cT2≥3cm, cT3, cT4 and/or cN+, with measurable disease and no prior treatment, age ≥18 and ≤70 years and Karnofsky Score ≥70% were eligible. Patients were randomized to AC (60/600 mg/m2 q3wk x 4 cycles) followed by T (100 mg/m2 q3wk x 4 cycles) without primary G-CSF prophylaxis, or to TAC (75/50/500 mg/m2 q3wk x 6 cycles) with primary G-CSF prophylaxis. If indicated, trastuzumab and/or endocrine therapy were given as adjuvant treatment. This present analysis focuses on the toxicity profile of the two treatment arms.
Results In total, 201 patients (n=100 AC-T, n=101 TAC) were included between February 2006 and April 2009. Baseline characteristics (AC-T/TAC) were well balanced. Patients in the AC-T arm had more frequently grade 3 / 4 toxicities as compared to the TAC arm, respectively in 57% and 28% (p=0.001). Grade 3 / 4 neutropenia without fever was more frequently reported with AC-T (35% vs. 4%; p=0.001). Grade 3 / 4 febrile neutropenia was also more frequent with AC-T (17% versus 5%; p=0.0062) and significantly increased during docetaxel treatment after AC. Notably, diarrhea was also more frequently seen in the AC-T arm (4% versus 0%, p=0.0423). Other grade 3 / 4 toxicities more frequently reported in the AC-T arm were neuropathy - sensory (5% vs. 0%; p=0.229) and pain other than muscle or bone pain (4% vs. 0%; p=0.0423). There were no grade 3 / 4 toxicities more frequently observed in the TAC arm.
Conclusion In the comparison of two taxane-anthracycline-cyclophosphamide regimens in the neo-adjuvant setting, it is observed that the sequential approach with a lower cumulative dose tends to have a slightly better efficacy outcome, but at the cost of increased grade 3 / 4 toxicity. However, considering the use of primary G-CSF prophylaxis in the TAC arm, and the fact that the incidence of febrile neutropenia was higher during taxane containing chemotherapy in the AC-T arm, the difference might (partly) disappear if primary G-CSF prophylaxis would be used in the sequential arm. Primary G-CSF prophylaxis may be considered during docetaxel if used sequentially after anthracycline-containing chemotherapy.
Support: Unrestricted grants from sanofi-aventis NL BV and Amgen BV.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-02.
P3-14-09: A Phase II Preoperative Study of Dasatinib, a Multi-Targeted Tyrosine Kinase Inhibitor, in Locally Advanced “Triple-Negative” Breast Cancer Patients.
Authors: Rimawi MF , Rodriguez AA , Yang WT , Gonzalez-Angulo AM , Nangia JR , Wang T , Speers C , Mills G , Hilsenbeck SG , Brown PH , Chang JC 
Published: June 2012

Abstract
Background: We previously reported that kinases (Src, Yes-1, cKIT, Abl, and EPH4) were druggable in triple negative breast cancer (TNBC). In this clinical trial, we sought to translate these findings by treating TNBC patients with dasatinib, a multi-targeted kinase inhibitor against these targets.
Methods: Women with stage II-III TNBC were eligible. Patients received dasatinib at 100 mg daily for 3 to 4 weeks before standard-of-care definitive surgery and chemotherapy. Biopsies were performed at baseline, week 1, and at the time of surgery. A cohort of patients had positron emission mammography (PEM; baseline and at 2–3 weeks of dasatinib therapy). This study was designed to detect an increase in clinical response rate from 10% to 25%, using a Simon optimal two stage design, with one-sided alpha=5% and power=80%. At least 3 responses out of 22 patients were needed to proceed to the second stage.
Results: 22 patients were enrolled (Table 1). Median tumor size was 7.0 cm (range 2.4-25 cm). Adverse events were modest, mainly grade 1–2 (headache: 45%, abnormal LFTs: 55%, GI: 23%, fatigue: 18%). One patient had a myocardial infarction 24 hours after starting dasatinib. Out of 22 patients, 2 (9%) had a clinical partial response after 3–4 weeks of therapy, 15 had stable disease (68%), while 5 had progressive disease (23%). Of the 8 patients who received paired PEM imaging, metabolic responses were observed in 2 patients (25%). Conclusion: A short course of dasatinib led to clinical responses in 2 out of 22 patients with TNBC, and the study did not proceed to second stage. Since TNBC is a heterogeneous disease, biomarker studies including sequencing of candidate genes like B-RAF for inactivating mutations might enable selection of those TNBC patients who could benefit from dasatinib.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-09.
P3-14-12: Local Control of Primary Breast Cancer Treated with Radical Radiotherapy Alone after Neoadjuvant Chemotherapy.
Authors: Makris A , Li SP , Ravichandran D , Ostler PJ , Pittam M 
Published: June 2012

Abstract
Introduction: The aim of this retrospective study was to evaluate the local recurrence rates in a cohort of patients who achieved a complete clinical response (cCR) to neoadjuvant chemotherapy and did not have surgery.
Materials and Methods: 148 women who achieved a cCR to neoadjuvant chemotherapy were identified from a prospectively maintained database (1995-2011) of 667 patients. 122 patients went on to have surgery (either wide local excision or mastectomy) followed by radiotherapy. In 26 patients (median age 49, range 35–72 years; T2-T4, N0-N3, M0), no surgery was performed but all received radical radiotherapy. Surgery was avoided due to either physician or patient choice. Recurrence was defined as first relapse of disease, either local (ipsilateral breast and/or axilla) or distant.
Results: All 26 patients who avoided surgery had neoadjuvant chemotherapy with 20 patients (77%) receiving anthracycline-based (FEC, FAC, ECF), 5 (19%) MMM and 1 (4%) CMF chemotherapy. The median number of cycles was 6 (range 4–8). Chemotherapy was followed by radical external beam radiotherapy to the breast +/− supraclavicular fossa and axilla (median dose delivered, 60Gy in 2Gy fractions). All were identified as operable at diagnosis including 3 patients who had supraclavicular lymphadenopathy. All 26 patients achieved a final cCR in the breast to chemotherapy. 21 patients had imaging with mammography and/or ultrasonography to assess radiological response at the end of neoadjuvant chemotherapy, of which 19 had a complete response and 2, a partial response. After a median follow-up of 144 months, 10/26 (38%) patients experienced local disease recurrence (2 also had distant recurrence) and 4/26 (15%) patients with distant metastases only. Patients with local recurrence only, went on to have a mastectomy whilst those with distant disease received systemic therapy. There were 10 deaths, 9 of which were breast cancer related (33%).
Conclusions: Local recurrence rates were high in patients achieving a cCR following neoadjuvant chemotherapy and who avoided surgery. Our practice has subsequently changed to include clip insertion and surgical excision on completion of chemotherapy. With increasing pathologic complete response rates to more active chemotherapy schedules (including taxanes +/− herceptin), it is being proposed that surgery could be avoided in selected patients. Our study shows that caution should be exercised.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-12.
P3-14-17: Paclitaxel, Carboplatin, and Trastuzumab in a Neoadjuvant Regimen for HER2−Positive Breast Cancer: The TRAIN Study.
Authors: Sonke GS , Mandjes IA , Holtkamp M , Schot M , Oosterkamp HM , Wesseling J , Vrancken Peeters M-JT , Rodenhuis S , Linn SC 
Published: June 2012

Abstract
Background: Treatment with trastuzumab is highly active in HER2 positive breast cancer, although cardiotoxicity is a well known side effect. The cardiotoxicity of trastuzumab may be aggravated by combined treatment with anthracyclines. Consequently, treatment with trastuzumab is often delayed pending the administration of anthracyclines. Both in vitro and in vivo data suggest that trastuzumab synergizes with a range of chemotherapeutic drugs, including taxoid drugs and carboplatin. In addition, prolonged pre-operative treatment leads to higher pathologic complete remission (pCR) rates. We report the results of a fase 2 trial integrating trastuzumab at the start of a non-anthracycline containing weekly paclitaxel-carboplatin based neo-adjuvant chemotherapy regimen in HER2−positive breast cancer. Patients and methods: One-hundred patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m2, carboplatin AUC=3 mg.ml-1.min, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24 only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. The trial was preceded by an initial pilot cohort of 55 patients treated with the same regimen.
Results: Final efficacy and safety results of all patients included in the phase 2 trial will be reported at the meeting. In the pilot cohort of 55 similarly treated patients, 33% had stage II disease, 69% was clinically node positive, and 49% was ER and PgR negative. Twenty-four patients (41%) had a pCR in breast and lymph nodes. pCR in ER negative patients was 67%, pCR in ER positive patients was 21%. The most commonly reported grade 3/4 toxicities were neutropenia (30%) and thrombocytopenia (27%). Dose reduction was required in 24% of the patients. Grade 3/4 left ventricular systolic dysfunction was not observed.
Conclusion: A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2 positive breast cancer with a good safety profile. A subsequent multicenter phase 3 trial will compare this regimen to a similar 16 week regimen preceded by 4 cycles of anthracyclines plus cyclophosphamide.
The study protocol was developed at the joint ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research in Flims, Switserland.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-17.
P4-01-16: The Influence of CYP2D6 Genetic Polymorphisms on Variability of Tamoxifen Metabolism in the Lebanese Breast Cancer Population.
Authors: Tfayli A , Zgheib N , Holail J , Habbal M-Z , Halawi R , El-Saghir N , Salem Z 
Published: June 2012

Abstract
Introduction The selective estrogen receptor modulator tamoxifen is commonly used for the treatment and prevention of breast cancer. Tamoxifen needs to be converted by the highly polymorphic enzyme, CYP2D6, to its active metabolites (4-hydroxytamoxifen and endoxifen) to exert its anti-estrogenic effect. Several clinical trials have shown that CYP2D6 poor metabolizers have decreased benefit from tamoxifen compared to extensive metabolizers. Large ethnic variations have been noticed in the frequency and effect of CYP2D6 polymorphisms.
Objectives To assess for the frequency of CYP2D6*3, *4, *5 (nonfunctional alleles with *5 being a gene deletion), *41 (reduced functional allele) as well as CYP2D6*x N (allele copy number) in a sample of Lebanese participants receiving maintenance doses of tamoxifen for early stage breast cancer, and to assess the effect of these polymorphisms on tamoxifen metabolism in the same subjects.
Methods 111 (median age= 48.7± 8.6years) Lebanese breast cancer women were recruited. Blood for isolation of DNA and measurement of tamoxifen metabolites was collected. CYP2D6 genotyping was performed using real-time PCR. Plasma levels of tamoxifen were being measured using HPLC.
Results The allele frequencies of CYP2D6*3, *4, and *41 were 0.9, 15.9 and 12.1 respectively. 18.9% of patients had more than 2 CYP2D6 copies and 9% had only 1 copy. Tamoxifen plasma concentration didn't significantly vary among the 4 phenotypic groups, although a trend was observed whereby PMs had the highest tamoxifen plasma concentrations and UMs had the lowest tamoxifen plasma concentrations (Tamoxifen median plasma concentrations in μg/L: PM=290, IM=210, EM=190 and UM=170). Furthermore, there was a statistically significant variation of Z-tamoxifen plasma concentrations among the phenotypic groups when PMs and IMs were grouped together: Z-tamoxifen median plasma concentrations in μg/L: PM+IM=130, EM=90 and UM=62 (P=0.03).
Conclusion This is the first study in the Middle East that evaluates the frequencies of CYP2D6 polymorhisms in a Lebanese breast cancer population and the effect of these polymorphisms on tamoxifen metabolism. We have shown that CYP2D6 phenotype is significantly correlated with Z-tamoxifen levels. PMs and IM group had the highest Z-tamoxifen plasma concentrations; in contrast UMs had the lowest Z-tamoxifen plasma concentrations. Further recruitment and follow up are being performed to assess for the role of these polymorphisms in disease outcome.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-16.
P4-01-20: Specific Anti-Proliferative Profile of Endoxifen for MCF-7 Cell Compared to 4-OH Tamoxifen.
Authors: Saji S , Hirose M , Hayashi S-I , Kuroi K 
Published: June 2012

Abstract
Background: Endoxifen and 4-hydroxy tamoxifen are both active metabolites of tamoxifen and exert anti-tumor activity for ER+ breast cancer. However, only small numbers of paper reported biological profile of endoxifen.
Methods: Cells were incubated with various concentration of endoxifen ( (Z)-4-Hydroxy-N-desmethyl Tamoxifen (&lt;10% with (E)-form)) for 6 days and viability (anti-proliferative index) was assessed by cell counting kit-8. For seeking the influence of ERβ, two independent ERβ expressing clones of MCF-7 cells were established by stable transfection of ERβ vesctor to MCF-7. Western blotting was done with ERα, ERβ, PgR and HER2 antibodies.
Results: IC50s of endoxifen for MCF-7 were 100 nM in estradiol (E2) deprivation condition and 500 nM in the presence of 1nM E2. These are significantly higher than those of 4-OH tamoxifen, which are 10 nM without E2 and 50 nM with E2, respectively. From the previous reports, plasma endoxifen concentrations in breast cancer patients were ranged from 20 to 200 nM according to CYP2D6 phenotype. Anti-proliferative index of 20 nM endoxifen for MCF-7 was 0.7 (indicating 30% reduction in proliferative activity), and 200 nM endoxifen was 0.5 in the absence of E2. These were 0.95 (20 nM) and 0.75 (200nM), respectively, when incubated with 1 nM E2. 10 nM 4-OH tamoxifen, which is mean concentration in patient plasma, showed about 0.6 anti-proliferative index with no regards to E2 condition. Without E2, endoxifen reduced ERα expression as previously reported, however, endoxifen increased ERα amount in the presence of E2 accompanied with decrease of HER-2 expression. This alternation of ERα and HER2 expression were identical to those observed using 4-OH tamoxifen. There was a weak tendency that ERβ expressing MCF-7 clones showed favorable response to endoxifen compared to parent MCF-7, but this was not significant.
Conclusion: Endoxifen is active agent for MCF-7 cell, however, it requires 10-fold higher concentration compared to 4-OH tamoxifen to achieve IC 50. Difference of anti-proliferative effect between 20 nM and 200 nM of endoxifen are relatively small, and it might result in minor difference for clinical response, as expected from recent clinical studies of CYP2D6. This is the first time to show that endoxifen has opposite effect to ERα protein level depending on the presence or absence of E2. ERβ expression did not enhance activity of endoxifen in contrast to previous report.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-20.
P4-01-22: Cyclin D1 and Its Prognostic Value in Planning of Endocrine Therapy for Women of Postmenopausal Age with Breast Cancer.
Authors: Skvortsov V , Manikhas A , Manikhas G , Oganesyan A , Raskin G 
Published: June 2012

Abstract
Background: Nowadays tamoxifen still remains the primary drug in breast cancer endocrine therapy. However, its application is limited due to the resistance of tumor cells. The search of adequate biomarkers is one of the most actual problems in prognosis of effectiveness of tamoxifen adjuvant therapy. The most perspective biomarker is cell cycle regulator cyclin D. Besides its central role in cell cycle regulation cyclin D1 modulates the estrogen receptors activity and can influence on the effectiveness of treatment with antiestrogenes and aromatase inhibitors.
The objective of our work was to evaluate the effectiveness of tamoxifen in adjuvant therapy of hormone-receptor-positive breast cancer in women of postmenopausal age with cyclin D1 expression.
Material and Methods: To evaluate the effectiveness of tamoxifen adjuvant application in women with cyclin D1-positive T1-4N0-3M0 breast cancer we have researched 2 retrospective groups of 70 patients that have been on regular medical check-up for a period of 5 years or that had previously undergone treatment. On the basis of the archive histological material we have revealed cyclin D1 in tumor cells.
Results: The expression of cyclin was classified in 4 levels: negative, low, moderate and high. Patients with lack of cyclin D1 expression or with low quantitative value (according to our data less than 30%) have no neoplastic process progression throughout the 5 years of tamoxifen adjuvant therapy. These women were both with axillary lymph nodes affection and without it (+N; -N). On the contrary, women with moderate and high cyclin D1 expression (more than 30%) had a relapse of tumor and distant metastasis is prognosed in 5 years of observation (p=0,005). Moderate level of cyclin D1 expression was observed in 45 (64%) patients and 28 (62%) of them had progression with metastasis in bones, 9 (20%) metastasis in soft tissues, 2 (4%) metastasis in lungs and 6 (14%) relapse in postoperative scar. High expression was revealed in 25 (35%) women and 17 (68 %) of them had bone affection, 7 (28%) soft tissue metastasis and 2 (4%) tumor relapse in postoperative scar. Lung metastasis were not observed. The average period of tumor relapse and progression of neoplastic process in patients with cyclin D1-positive breast cancer is 20 months. Discussion: The results of our work suggest that women with hormone-receptor-positive cyclin D1-negative breast cancer on early stages have more prolonged non-relapse period during the tamoxifen adjuvant therapy. Patients with cyclin D1-positive breast cancer are less sensitive to tamoxifen treatment and in adjuvant regime should receive therapy with other effective equivalent drugs (aromatase inhibitors).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-22.
P4-02-09: Estrogen-Related Receptor a Mediates Insulin-Like Growth Factor-I Dependent Migration in Breast Cancer Cells.
Authors: Fettig-Anderson LM , Oh AS , Yee D 
Published: June 2012

Abstract
The orphan nuclear estrogen-related receptors (ERR) have homology to steroid hormone receptors. Unlike classical steroid hormone receptors, ERRs do not have known ligands but are transcriptionally activated upon binding to nuclear receptor coregulators such as PGC1α, PGC1β, and PPRC1. ERRs regulate energy metabolism and are accordingly expressed in tissues that require high energy production. ERRs recognize their own ERRE (estrogen-related receptor response element) gene promoters, but can also activate transcription via ERE (estrogen receptor response element) promoters, representing the ability of ERRs to cross participate in ERα regulatory pathways in the absence of estrogen. Of the three family members (α,β,γ), ERRα is the most highly expressed in breast tissue. ERRα expression was found to be increased in ERα negative breast cancers and associated with poor prognoses. ERRα and its coactivators can increase the expression of a critical mediator of breast tumor angiogenesis and metastasis, VEGFA. We have previously shown that VEGFA is regulated by insulin and IGF receptor activation and hypothesized that ERRα may be a mediator of this finding. We therefore explored whether ERRα and its coactivators are necessary for IGF-I/insulin dependent regulation of VEGFA and cell migration. ERRα was expressed in breast cancer cell lines, but no correlation was observed with breast cancer subtypes. Reducing endogenous ERRα levels by shRNA reduced IGF-I dependent migration in MDA-MB-231 cells. These results were confirmed using an ERRα specific inverse agonist (XCT-790), which also inhibited MDA-MB-231 cell migration. Modulating ERRα mRNA levels via shRNA resulted in decreased VEGFA mRNA levels in MCF7L cells and increased VEGFA mRNA levels in MDA-MB-231 cells, while the inverse agonist XCT-790 caused an increase in VEGFA mRNA levels in both cell lines. Reducing ERRa levels did not affect the expression of the IGF1R, InsR, IRS-1, IRS-2, PI-3K-Akt-mTOR dependent signaling pathway. Neither ERRα protein nor mRNA levels were modulated by IGF-I or insulin. We conclude that ERRα is important for mediating IGF-I dependent migration, but have shown that ERRα is not directly regulated by the IGF signaling. We will next explore the role of ERRα's coregulators (PGC1α, PGC1β, and PPRC1) in the regulation of VEGFA by the IGF/insulin pathway given their central role in regulating ERRα's function.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-09.
P4-02-10: The Relationship between Estrogen Receptor Gene Polymorphism and Mammographic Density in Postmenopausal Women.
Authors: Baldisserotto FDG , Elias S , Silva IDCG , Nazario ACP 
Published: June 2012

Abstract
Background Assess the relation between the presence of PVUII and XBAI polymorphisms in the estrogen receptor alpha gene and mammographic density in postmenopausal women.
Methods For the present analysis, 189 postmenopausal women who had never used hormonal therapy and who did not have clinical or mammographic features were selected. Based on the ACR-BIRADSâ 2003 classification, the mammographic density was determined by three independent readers (two subjective ratings and one computerized - Adobe Photoshop â 7.0 software). Blood samples were available to extract DNA according to KIT GFX â protocol. PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) was then used to identify the polymorphisms.
Results There was a high degree of agreement among the three readers to determine the mammographic density (Kappa&gt;0.75). Sixty women (32%) had dense breasts and 129 (68%) had non-dense breasts. The PVUII polymorphism was found in 132 (69.8%) of 189 women, while the XBAI was found in 135 (71.4%) of women. Parity (p=0.02) and body mass index (p&lt;0.0001) were associated with mammographic density. It was observed that for the XBAI polymorphism, women with two mutated alleles were approximately 2.5 times more likely to be classified in dense breasts group (p=0.003) and the presence of both wild alleles was associated with fibroglandular tissue replacement by fat (p=0.02).
Conclusions There was no significant association of the PVUII polymorphism in the estrogen receptor alpha gene with mammographic density (p=0.34). However, the XBAI polymorphism was observed at a higher mutated homozygous frequency in women with dense breasts and there was an increased frequency of wild-type homozygous and heterozygous women with fat-replaced breasts (p=0.01).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-10.