bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor necrosis factor transactivates ErbB2 in breast cancer cells.
Authors: Rivas MA , Tkach M , Proietti CJ , Rosemblit C , Beguelin W , Sundblad V , Díaz Flaqué MC , Charreau EH , Elizalde PV , Schillaci R 
Published: December 2010

Abstract
Abstract #4056
We have previously shown that TNFα induces proliferation of the murine mammary adenocarcinoma C4HD through activation of the PI-3K/Akt signaling pathway that converges on the transcriptional activation of NF-κB. Since C4HD tumor overexpresses ErbB2 and given that this tyrosine kinase plays a critical role in C4HD cell proliferation, we wondered whether interactions between TNFα and ErbB2 could be taking place. Our findings revealed that treatment of C4HD cells with the ErbB2 inhibitor AG825 blocked TNFα-induced proliferation. Similar results were obtained using the human ErbB2-overexpressing cell line SK-BR-3. Then, we studied the effect of TNFα on ErbB2 phosphorylation in C4HD and SK-BR-3 cells. We found that TNFα increased total ErbB2 tyrosine phosphorylation in C4HD and SK-BR-3 cells, as well as on the specific residues tyrosines 927 and 1172 in murine cells and on its human homologues 877 and 1222. These effects where not caused by the release of ErbBs ligands from the cell membrane by TNFα, since treatment with the metalloprotease inhibitor GM6001 did not affect TNFα-induced ErbB2 phosphorylation. We then studied if c-Src was involved in the above effect given that it is known to directly phosphorylate ErbB2 in the Tyr 877 residue. We found that addition of PP2, a Src family inhibitor, completely inhibited phosphorylation of Tyr 927/877 ErbB2, and that to a lesser degree it inhibited Tyr 1172/1222 ErbB2 in both cell types. We also performed an in vitro cold phosphorylation assay where we observed that c-Src immunoprecipitated from C4HD cells treated with TNFα was able to phosphorylate ErbB2 on Tyr 927 residue. Taken together, these results indicate that TNFα induces phosphorylation of ErbB2 at Tyr877/927 residue and that c-Src is the tyrosine kinase involved in this effect. In addition, we observed that upon TNFα stimulation, ErbB2 associated with ErbB3 leading to PI-3K/Akt pathway activation. Treatment of cells with AG825 inhibited Akt and NF-κB activation by TNFα, as evidenced by western blots of phospho proteins and reporter gene studies, respectively. The above data for the first time identify TNFα as a cytokine able to transactivate ErbB2, disclosing c-Src involvement in such effect. Also we demonstrated that TNFα ability to activate Akt and NF-κB transcriptional activation is dependent on ErbB2 phosphorylation in breast cancer cells that overexpress ErbB2. Interestingly, TNFα appears as a new player in ErbB2-overexpressing breast tumors, and its eventual worth as a prognostic factor in anti ErbB2 therapy is yet to be determined.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4056.
Bone morphogenetic protein 10 (BMP-10) inhibits growth of breast cancer cells and correlates with poor prognosis.
Authors: Ye L , Kynaston HG , Mansel RE , Jiang WG 
Published: December 2010

Abstract
Abstract #4068
Background: Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and are known to be involved in the development of bone metastasis from solid tumours. Recent studies have shown that BMP-10 plays some critical roles during the fetal or postnatal development, particularly during the morphogenesis of heart. However, its role in cancer is largely unknown. The present study investigated the role of BMP-10 in breast cancer cells and pattern of expression in clinical breast cancers.&#x2028; Methods: The expression of BMP-10 was examined in a cohort of human breast cancer specimen (normal, n=23; cancer, n=97), using both quantitative real time PCR and immunohistochemical staining. Levels of BMP-10 transcripts were correlated with clinical and pathological, together with clinical outcome information of the patients. A human BMP-10 expression construct was used to transfect breast cancer cells (MDA-MB-231, negative in BMP-10 expression). The expression of BMP-10 in the transfected cells was verified using RT-PCR and western blot. The effect of BMP-10 expression on growth of MDA-MB-231 cells was investigated using an in vitro growth assay.&#x2028; Results: Immunohistochemical staining revealed a decreased protein expression of BMP-10 in breast cancer cells, compared with normal mammary epithelial cells. The quantitative real time PCR further demonstrated that low levels of the BMP-10 transcripts correlated to poor prognosis. Tumours form patients with good prognostic index (NPI&lt;3.4) had significantly higher levels of BMP-10 transcripts, compared with those from poor prognostic index (NPI&gt;5.4) (p=0.045). In addition, patients who died of breast cancer showed a significantly lower levels of the transcript compared with those who remained disease free (p=0.027). Mean disease free survival of the patients with higher level of BMP-10 was 132.8 (122.0-143.5, 95% CI) months, which was significantly longer compared to 93.7 (60.3-127.2) months of patients with lower level of BMP-10 expression, p=0.043 using Kaplan-Meirer survival analysis. An inhibitory effect on cell growth by over-expression of BMP-10 was seen in the breast cancer cells. The absorbance of MDA-MB-231 BMP-10 over-expressing (MDA-MB-231BMP-10exp) cells of Day 5 is 1.40±0.19, p&lt;0.01 vs both MDA-MB-231 wild type (MDA-MB-231WT, 2.17±0.11) and empty vector control (MDA-MB-231pEF/His, 1.83±0.17).&#x2028; Conclusions: Taken together, BMP-10 can inhibit the cell growth of breast cancer cells. A decrease in BMP-10 expression correlates with poor prognosis of patients with breast cancer. BMP-10 may function as tumor suppressor in breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4068.
Consistent TP53 mutations in BRCA1 and sporadic basal-like breast tumors, while infrequent in luminal BRCA1 tumors.
Authors: Manié E , Vincent-Salomon A , Lehmann-Che J , Pierron G , Turpin E , Warcoin M , Gruel N , Lebigot I , Sastre-Garau X , Delattre O , de Thè H , Stoppa-Lyonnet D , Stern M 
Published: December 2010

Abstract
Abstract #4070
Breast tumors with a germline mutation of BRCA1 (BRCA1 tumors) and Basal-Like Carcinoma (BLC) have been shown to be associated with a high rate of TP53 mutations. Because it has also been shown that BRCA1 tumors frequently display a basal-like phenotype, we sought to determine whether TP53 mutations were correlated to the hereditary BRCA1 mutated status or to the particular histological type of these tumors. We first explored the status of the TP53 gene in a series of 28 BRCA1 BLCs using immunohistochemistry, direct sequencing of the coding sequence, and functional assay in yeast (FASAY), and compared it to the status of TP53 in 27 series of sporadic (non hereditary) BLCs. With this sensitive approach, TP53 was found consistently mutated in BRCA1 (28/28) and sporadic (26/27) BLCs. However, mutation spectrum was different, in particular with a much higher rate of insertion/deletion in BRCA1 BLCs (12/27) than in the sporadic group (2/25). Secondly, we analyzed the incidence of TP53 mutations in 10 BRCA1 luminal tumors, using the same strategy. Surprisingly, only 3 of these 10 tumors were mutated, a frequency similar to that found in matched sporadic luminal tumors. In conclusion, TP53 mutation is a mandatory event in BRCA1 or sporadic BLCs, but not a common feature of BRCA1 luminal tumors.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4070.
Breast cancer patients unknowingly dosing themselves with estrogen by using topical moisturizers.
Authors: Olson AC , Link JS , Kupiec TC 
Published: December 2010

Abstract
Abstract #4087
Background: Topically applied estrogens are more efficiently absorbed into the body than estrogens administered orally, due to the first pass effect by the liver. Estrogen receptor positive breast cancer patients need to avoid exogenously administered estrogen to minimize chance of recurrence. This is especially significant for women on aromatase inhibitor treatment,where topical estrogen may overcome the therapeutic effect. Also, non breast cancer patients using estrogen containing topical moisturizers may be unknowingly dosing themselves daily with estrogen, often for years, increasing their chances of developing breast cancer.&#x2028; Materials and Methods: Sixteen different topical moisturizers were purchased or donated from department stores or chain drugstores. None of the creams noted any estrogen content in their list of ingredients. Each of the sixteen commercial products was analyzed for estradiol, estriol and estrone utilizing High Performance Liquid Chromatography (HPLC). HPLC is commonly used in the pharmaceutical industry to provide component analysis. Detection was carried out through use of a Variable Wavelength Detector (VWD) and a Diode Array Detector.&#x2028; Results: Four samples contained greater than 0.40% estriol, one contained 0.17% estriol, and one contained 0.05% estrone, despite having no listing on the ingredient list.&#x2028; Discussion: Topical estrogens are considered effective in enhancing the “youthful look” of aging skin. Manufacturers are marketing incompletely labeled moisturizers containing estrogens. Consumers are unaware their moisturizer may be providing them with unwanted systemic estrogen exposure. The FDA cosmetics division is not presently testing for this potential risk for breast cancer patients. Other breast cancer advocacy groups and the FDA need to promptly repeat these procedures and also check for exotic "designer" estrogens.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4087.
Pre operative assessment enables the early detection and treatment of shoulder impairments related to breast cancer treatment.
Authors: Stout Gergich NL , Levy E , Springer B , Pfalzer L , McGarvey C , Gerber L , Soballe P 
Published: December 2010

Abstract
Abstract #4091
Background: Early detection and management of impairments and limb dysfunction after breast cancer treatment contribute to more successful functional outcomes. Health care providers should be encouraged to provide a pre-operative screening visit to ascertain the patient's baseline physical function measures. Patients should then be followed prospectively at regular intervals during and after treatment for early identification of impairments and to provide intervention while the functional limitations are minimal, thereby preventing long term loss of function.&#x2028; Materials and Methods: A prospective, observational study (n=196) with interval follow up over one year assessed the effects of an early identification and intervention model of physical therapy care on women after breast cancer treatment. Measurement of upper extremity (UE) function included; active range of motion (ROM), strength, and limb volume as measured by the optoelectronic volumeter (Perometer®), and self-reported physical activity disability. Individuals were seen for an initial visit prior to surgical treatment and followed-up at approximately one month post-operatively and at three month intervals thereafter, up to 18 months. Patients received a general home exercise program pre-operatively and instructed to initiate at 2 weeks post op. If impairments were identified at any of the follow up visits, physical therapy intervention was prescribed.&#x2028; Results: A significant decrease in active shoulder ROM was noted at one month post-op as compared to baseline measurement in 102 patients. This significance resolved at the 12+ month follow up visit. Loss of shoulder ROM correlated with other UE treatment related morbidities including; axillary web syndrome, seroma and pain.&#x2028; Discussion: Incidence of upper extremity morbidity after breast cancer treatment is documented as high as 70%. This study clearly demonstrates the potential for substantial reduction in UE dysfunction related to breast cancer treatment when using an early identification and intervention model. Many morbidities such as pain, reduced range of motion, decreased strength and sub-clinical lymphedema can be detected early and managed with minimal, cost-effective intervention. Additional research is needed to assess ways of maintaining this cost effective model of care in the long-term.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4091.
Adjuvant dose-dense doxorubicin-cyclophosphamide x 4 with or without bevacizumab is safe: no evidence of short-term changes in left ventricular ejection fraction.
Authors: Morris PG , Dickler M , McArthur H , Traina T , Godfrey L , Steingart R , Rugo H , Lin N , Moy B , Come S , Sugarman S , Norton L , Hudis CA , Dang C 
Published: December 2010

Abstract
Abstract #4102
Background&#x2028; Dose-Dense (dd) doxorubicin-cyclophosphamide (AC)-paclitaxel (P) is superior to q3w AC-P. Both are associated with a &lt;1% incidence of congestive heart failure (CHF). The advent of targeted therapies potentially raises the risks of cardiac toxicity. We have, therefore, conducted 3 sequential safety studies using ddAC → P, one of which included bevacizumab (B) concurrently with ddAC. Here we report the cardiac safety of ddAC alone or with B.&#x2028; Methods&#x2028; Patients with HER2-positive breast cancer were treated on successive trials of ddAC → P and trastuzumab (T) (left ventricular ejection fraction (LVEF) &gt; 55%) and ddAC → PT-lapatinib (LVEF &gt; 50%). Patients with HER2-normal breast cancer were treated with B-ddAC → B-nanoparticle albumin-bound-P (LVEF &gt; 50%). In all 3 trials LVEF was measured by MUGA scan at enrolment and at month 2 following completion of ddAC x 4. Prospective cardiac safety assessments before and after q 2 week AC x 4 were aggregated to determine the acute risks of cardiac dysfunction.&#x2028; Results&#x2028; From Jan '05 to May '08 236 pts were enrolled in 3 trials. Median age was 47yrs (range 27-75). Median LVEF pre-ddAC was 68% (range 52-82%). LVEF post-ddAC is available in 233 pts (99%) (1 pt withdrew consent, 1 progressive disease, 1 died from viral pneumonia). Median LVEF was unchanged at 68% (range 47-81%). No pt developed symptomatic CHF. Two pts had asymptomatic LVEF decline &gt;15%: 1 pt (post B-ddAC) had decline from 71 to 53%, which improved to 64% in 4 wks and 1 pt (post ddAC) had decline 68% to 47%, which improved to 64% in 4 wks. No other pt had asymptomatic LVEF decline below 50%. Five of six pts with LVEF declines of 10-15% had improvement in LVEFs and continued treatment while 1 withdrew consent. Post-ddAC LVEF was similar whether or not pts received B.&#x2028; &#x2028; Conclusions&#x2028; Previously reported high rates of asymptomatic LVEF post q3w AC leading to pt dropout were not seen in these studies of ddAC or B-ddAC. Post-ddAC LVEFs were similar with or without concurrent bevacizumab. Dose-dense AC is safe and not associated with frequent acute changes in LVEF regardless of the concurrent use of B.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4102.
Feasibility of the sequential FEC 100-Taxotere chemotherapy regimen as an adjuvant or neoadjuvant treatment for breast cancer. Experience of a single institution.
Authors: Cousin S , Mailliez A , Servent V , Vanlemmens L , Vennin P , Jacques B 
Published: December 2010

Abstract
Abstract #4110
The sequential treatment of 3 FEC 100- 3 Taxotere is one of the standard treatments in the adjuvant and neoadjuvant settings. However , if the general tolerability of this regimen is acceptable, few studies have been devoted to the hematological toxicity outside of clinical trials and to the need of Granulocyte growth factors (GCSF)&#x2028; Patients and methods: We studied the incidence of grade 3 and 4 neutropenia observed at D1 of each cycle and of febrile neutropenia induced by the FEC100 -Taxotere regimen in 284 patients (1757 chemotherapy cycles). Side effects were graded according to NCI criteria. The relative dose intensity (RDI) was the ratio between the dose received by each patient and the duration of treatment between the first dose and 3 weeks after the last administration. GCSF were given according to the recommendations, mostly after febrile neutropenia.&#x2028; Results: 1757 cycles were administered; 23 (1.3%) were deleted mostly because of non hematological toxicities due to Taxotere. A febrile neutropenia (hyperthermia and grade 4 neutropenia) was observed in 0.1% of the FEC100 cycles and in 0,7% after Taxotere. In about 2/3 of the cases febrile neutropenia was observed at the first cycle. Hyperthermia and grade 3 neutropenia was observed in 0,6% of the cycles after FEC100 and 0,2% after Taxotere. A RDI of more than 85% was observed for the overall treatment in 84% of the patients, for FEC100 in 91%, for Taxotere in 76 %. Granulocyte growth factors were used in 76 cycles. The efficacy results according to RDI after neoadjuvant treatment (n= 115) will be presented.&#x2028; Discussion and Conclusion: This study confirms the results previously published (Debled 2007).The hematological tolerability of the FEC100-Taxotere regimen is acceptable without GCSF. Nevertheless, febrile neutropenia occurs essentially at the first cycle, risk factors should be looked for and this particular patient population might benefit of GCSF. Furthermore, up to 16% of the patients receive less than 85% of the theoretical dose, essentially due to neutropenia and might also benefit of a treatment with GCSF.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4110.
Relative dose intensity reduction in breast cancer adjuvant chemotherapy.
Authors: Faustino C , Afonso N , Sousa B , Espírito Santo J , Rodrigues H 
Published: December 2010

Abstract
Abstract #4111
Introduction&#x2028; In breast cancer (BC), adjuvant chemotherapy has become a standard therapy, resulting in prolonged survival. This goal might be affected by chemotherapy dose reductions and delays that are not uncommon features.&#x2028; The aim of this study was to assess relative dose intensity (RDI) reduction risk factors and define predictive factors.&#x2028; Methods&#x2028; Data regarding BC patients (pts) under anthracycline based-chemotherapy regimens was collected, retrospectively, from two Portuguese centres, between 1998 and 2007, and combined into a database of 783 individuals. Primary G-CSF prophylaxis was not planned. DIEP® (Dose Intensity Evaluation Programme) software was developed to allow calculation of RDI, and includes demographic data, clinical and treatment characteristics, chemotherapy dose modifications and delays, haematological toxicities and patterns of use of G-CSF.&#x2028; Univariate and multivariate analysis was performed to identify factors related to RDI ≤ 90% in these patients. A value of P &lt; 0.05 was considered of statistical significance.&#x2028; Results&#x2028; Pts distribution according to chemotherapy: doxorubicin/cyclophosphamide (A60 C600) – 31,5%, 5-fluorouracil/epirubicin/cyclophosphamide (F500 E100 C500) – 19,2%, 5-fluorouracil/doxorubicin/cyclophosphamide (F500 A50 C500) – 49,3%. A RDI ≤ 90% was frequent across all chemotherapy regimens, but most common in pts receiving FEC (34,7%) and AC (23,5%) regimens.&#x2028; According to univariate analysis, factors related to reduction of RDI were: age ≥ 65 years (P = 0,006), node positive (P = 0,037), chemotherapy regimen (P &lt; 0,001), number of pts with at least one G-CSF administration on secondary prophylaxis (P = 0,015), number of pts with at least one G-CSF administration due to neutropenia or febrile neutropenia (P &lt; 0,001 ) and number of pts with at least one hospitalization due to febrile neutropenia (P &lt; 0.001). In multivariate analysis, independent predictors of RDI ≤ 90% were: AC regimen (P = 0,008), FEC regimen (P = 0,002), age ≥ 65 years old (P = 0,018), node positive (P = 0,016) and at least one hospitalization due to febrile neutropenia (P &lt; 0,001).&#x2028; Conclusion&#x2028; A considerable number of our BC pts, submitted to anthracycline based-chemotherapy, continue to experience RDI reductions. Most affected pts were more than 65 years old, or under FEC or AC regimens, or had node positive tumors. This data might help to identify a subgroup of BC pts that benefit from primary prophylaxis with G-CSF.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4111.
Phase 2 study of dual VEGF/HER2 blockade with pazopanib + lapatinib in patients with first-line HER2 positive advanced or metastatic (adv/met) breast cancer.
Authors: Slamon DJ , Stemmer SM , Johnston S , Kim S , Durante M , Pandite LN , Roychowdhury DF , Goodman VL 
Published: December 2010

Abstract
Abstract #4114
Background: Evidence indicates a direct molecular link between HER2 amplification and up-regulation of VEGF in HER2+ breast cancer. Concurrent over-expression of HER2 and VEGF is associated with a poorer clinical outcome than over-expression of either alone. These data provide the rationale for simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (Tykerb®) (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluated the efficacy and safety of dual pathway inhibition in patients (pts) with HER2+ adv/met breast cancer.&#x2028; Methods: Eligible pts received no prior chemotherapy or HER2-directed therapy for met disease and had measurable disease per RECIST. Pts were enrolled in one of 2 cohorts. In cohort 1 (C1), pts were randomized to P 400 mg/d + L 1000 mg/d or L alone (1500 mg/d). Enrollment to cohort 2 (C2) began after completion of enrollment to C1. In C2 pts received the combination at doses of P 800 mg/d and L 1500 mg/d. Following disease assessment at week (wk) 12, pts with an objective response could continue on study treatment following re-consent; those with stable disease could continue only where trastuzumab was unavailable. The primary endpoint of C1 was progressive disease rate (PDR) at wk 12 in HER2 FISH+ pts. The primary endpoint of C2 is week 12 response rate in HER2 FISH+ pts.&#x2028; Results: 140 pts were included in the randomized cohort analysis which was previously reported [J Clin Onc 26:2008 (May 20 suppl; abstr 1016)]. Enrollment in C2 has been completed; 40 pts (36 confirmed FISH+) have been enrolled. A preliminary safety analysis has been performed. The most common adverse events of any grade were diarrhea, nausea, fatigue, hypertension, and rash. The most common laboratory abnormalities were ALT and AST increase. Efficacy data will be analyzed when the last pt has completed the week 12 assessment.&#x2028; Conclusion: This is the first Phase II trial to evaluate the combination of 2 oral targeted agents in first-line Her2+ adv/met breast cancer. The lower dose combination demonstrated improved response rate compared to L monotherapy. Previously unreported efficacy and safety data from the higher dose cohort will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4114.