bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase Ib Trial of Erlotinib, an EGFR Inhibitor, and Everolimus (RAD001), an mTOR Inhibitor, in Patients with Metastatic Breast Cancer.
Authors: Mayer I. , Means-Powell J. , Shyr Y. , Arteaga C. 
Published: December 2010

Abstract
Background: The EGFR and the PI3K pathways have been implicated in breast cancer's prognosis and mechanisms of resistance to conventional therapies. Preclinical data have shown synergy between EGFR and PI3K/Akt pathway blockade. Therefore, we conducted a phase Ib trial to determine the maximum tolerated dose (MTD) and antitumor activity of Erlotinib, an oral EGFR tyrosine kinase inhibitor, and Everolimus (RAD001), an oral mTOR inhibitor, given daily to patients with metastatic breast cancer.Materials and Methods: This was an open-label, phase I dose-escalation study. Everolimus was started at 2.5 mg/d and Erlotinib was started at 100 mg/d on a 28-day treatment cycle. Doses were escalated over 6 levels (Everolimus 2.5, 5 or 10 mg daily with Erlotinib 100 or 150 mg daily). Treatment was continued until consistent dose-limiting toxicity (DLT) was observed or until progression of disease. All toxicities were documented using the NCI CTC v.3. Disease assessment was done every 2 months after initiation of therapy.Results: A total of 14 patients were enrolled on the first 2 dose levels (Erlotinib 100 mg with Everolimus 2.5 mg [level I] and 5 mg [level II] daily). Eight patients were enrolled on level I and 6 patients were enrolled on level II. The median age of all patients enrolled was 55 years of age, and 92% of them had visceral disease. Half of the patients had ER+ disease, 35% had HER2 + disease, and 15% had triple-negative disease. The median number of previous chemotherapy regimens in the metastatic setting was 4. Two patients on the level II cohort discontinued trial due to grade 3 stomatitis prior to their first disease assessment. Of the remaining 13 patients, 11 progressed at the time of their first disease assessment, and 1 patient on the dose level I cohort had a partial response that lasted for 7 months. The most common toxicities were rash (16%), transaminase elevation (15%), stomatitis (13%), fatigue (7%) and diarrhea (5%). Grade 3 and 4 toxicities were overall uncommon (3.5%), and mostly consisted of stomatitis, transaminase elevation and rash. Stomatitis was the only DLT, and was seen at dose level II. The MTD was determined to be Erlotinib 100 mg and Everolimus 2.5 mg daily.Discussion: In patients with metastatic HER2-negative breast cancer the combination of Erlotinib and Everolimus was overall well tolerated, but clinically ineffective from a tumor activity point of view in this heavily pre-treated patient population. Stomatitis was one of the most common toxicities and also the DLT in the cohort treated with dose level II. In view of the plethora of novel active agents currently in clinical trials in breast cancer, we do not believe the above combination warrants further testing in this disease.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3094.
Comparison between Nipple-Areola Saving Subcutaneous Mastectomy and Conventional Subcutaneous Mastectomy in Local Relapse and Prognosis: 5 Year Follow-Up Results.
Authors: Kang S. , Jeon Y. , Kim C. , Cho Y. , Lee S. 
Published: December 2010

Abstract
Backgrounds: Skin-sparing mastectomy (SSM) and the even more conservative nipple-areola-skin sparing mastectomy (NASSM) are surgical options for selected patients with indication for mastectomy. But long term result of NASSM is rare and there is no report in Korea. So, we report here 5-year follow-up results of NASSM.Materials and Methods: 202 patients who underwent SSM (N=67) or NASSM (N=135) for breast cancer at our institution between 1996 and 2006 were included in analysis. All patients were followed-up completely. For making a decision of preserving the nipple-areola complex (NAC) during operation, frozen section analysis of the retroareolar glandular tissue with precise localization was done after meticulous dissection of parenchyme under the areola. In the case of positive result in the frozen section or final histology in the NAC, NAC was sacrificed. Intra- or postoperative radiotherapy was not performed. Local relapse (LR) rate and disease free survival (DFS) was analyzed and compared the result between NASSM and SSM.Results: The mean age at diagnosis was 40.2 years old (range 24-65) and mean follow-up months of NASSM was 70.9 months and 60.5 months in SSM. 60 NACs (29.7%) of the all objective NACs were involved by cancer cell at the final histology. The cancer cell involvement to the NAC were more common in invasive carcinoma with extensive intraductal component (p&lt;0.001) or ductal carcinoma in situ component (p=0.048). But tumor size, vascular invasion and nodal status did not affect to involvement of the cancer cell in the NAC. Local recurrences occurred in 8.9% (NASSM) and 6.0% (SSM) of all patients, but there was no significant correlation between the two procedures (p&gt;0.05). Local recurrences occurred at NAC (8 cases), skin flap (3 cases) and chest wall (1 cases) in NASSM procedure group, and 4 skin flaps in SSM group. All NAC recurrences were treated by wide excision of NAC. After treatment of local recurrence, only one case of SSM group preceded to distant metastasis. 5 year Disease-free survival rate was 88.2% in NASSM and 88.4% in SSM group (p&gt;0.05).Conclusion: Our long term follow-up study shows that Nipple-areola-skin sparing mastectomy is oncologically safe procedure for breast cancer in patients who are candidates for mastectomy. Even if relapse is occurred in the NAC, this recurrence cannot affect to the progression of relapse after adequate local treatment. Thus, NASSM is alternative method for SSM with oncological safety and better cosmetic outcome.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3105.
Eleven-Year Follow-Up of a Randomised Study of Pectoral Fascia Preservation after Mastectomy for Early Breast Cancer.
Authors: Dalberg K. 
Published: December 2010

Abstract
Background: In a previous report with 6 years follow-up a trend towards an increased risk for chest wall recurrence was seen in breast cancer patients operated with preserved pectoral fascia compared to removal of the pectoral fascia. The aim of the present study was to assess whether the preservation or removal of the pectoral fascia in the modified radical mastectomy procedure had any impact on survival or local control in breast cancer patients when followed long term.Method: The trial included 247 patients with breast cancer who underwent modified radical mastectomy in five Swedish hospitals 1993-1997. The median follow-up time was 11 years. The patients were randomised between removal (n=122) versus preservation (n=125) of the pectoral fascia.Results: The breast cancer specific survival at 10 years was 75%. Removal or preservation of the pectoral fascia had not any significant impact on the chest-wall recurrence and on breast cancer specific survival. A total of 18 patients with chest-wall recurrence were seen in the group allocated to pectoral fascia preservation versus 10 in patients allocated to pectoral fascia removal (hazard ratio=1.8, 95%CI = 0.8-4.0). The majority of the chest-wall recurrences were detected 0-5 years postoperatively. The cumulative chest-wall recurrence rates at 5 and at 10 years were 13 and 15% respectively in patients allocated to pectoral fascia preservation and 8 and 9% in patients allocated to pectoral fascia removalConclusion: Neither the chest-wall recurrence rate nor the breast cancer specific survival is significantly influenced by the preservation of the pectoral fascia when the tumor macroscopically does not involve the muscle.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3109.
Assessment of the Likelihood of Invasive Breast Cancer When Core Needle Biopsy Shows DCIS.
Authors: Kurniawan E. , Rose A. , Mou A. , Buchanan M. , Collins J. , Wong M. , Miller J. , Mann G. 
Published: December 2010

Abstract
Background: Ductal carcinoma in-situ (DCIS) on core needle biopsy (CNB) may be associated with a final diagnosis of invasive cancer (IC). As patients with IC need axillary assessment, those at risk of upstaging may be appropriate for sentinel node biopsy (SNB) at initial surgery, preventing the need for re-operation. We assessed this risk using pre-operative factors to develop a management algorithm.Materials and Methods: All patients whose CNB showed DCIS or DCIS with microinvasion (DCISm) from a single population-based breast screening program in Australia between 1994 and 2006 were studied. Medical records were reviewed for demographic, radiologic, clinical and pathologic data.Results: 11 of 15 DCISm cases (73.3%) and 65 of 375 DCIS cases (17.3%) were upstaged to IC. Microinvasion on CNB overwhelmingly predicted presence of frank invasive cancer. For cases of DCIS, multivariate analysis showed that (1) palpability (p=0.009), (2) large mammographic size ≥20mm (p=0.001) and (3) prolonged screening interval ≥3 years (p=0.008) were associated with upstaging. On univariate analysis, (4) non-calcific mammographic features (mass, architectural distortion or non-specific density) were significantly associated with upstaging (p=0.001). There was a trend towards upstaging in patients with high grade DCIS on CNB (p=0.07). Factors not associated with upstaging were microcalcifications (p=0.12), comedonecrosis (p=0.14), age (p=0.38) and CNB method (p=0.50). The rate of upstaging increases with the number of associated risk factors present in a patient: 8.3% in patients with no risk factors, 21.2% in those with one risk factor, 38.6% in those with two risk factors, and 52.9% in those with three risk factors. 13 patients (3.3%) had lymph node metastases.Conclusions: The risk of upstaging can be estimated using pre-operative features in patients with DCIS on CNB. We propose a management algorithm that includes SNB for DCIS patients: with microinvasion on core biopsy, with two or more predictive factors, and those with planned total mastectomy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3111.
Impact of Primary Site Surgical Resection on Survival in Stage IV Breast Cancer.
Authors: Ahn S. , Han W. , Min J. , Bae J. , Ko E. , Yu J. , Noh D. 
Published: December 2010

Abstract
Background: Currently, primary treatments for stage IV breast cancer are radiation and systemic therapy which include chemotherapy, endocrine therapy and targeted therapy. Surgical resection of primary tumor is usually done for tumor-related complications. A recent review suggested that surgery may improve long-term survival in stageIV breast cancer patients. We evaluated the impact of primary site surgical resection on survival in such patients.Material and Methods: We reviewed the records of stage IV breast cancer patients treated at Seoul National University Hospital between 1992 and 2008. Clinical and tumor characteristics, systemic and local treatments were compared for the surgically versus nonsurgically treated patients.Results: Of 199 patients identified, 111(55.8%) recevied surgical excision of their primary tumor and 88(44.2%) did not. The mean survival of surgically treated patients was 67 months versus 52 months for patients those who did not(p=0.0276). In multivariate analysis, after adjustment for ER status, visceral metastasis, number of metastatic sites and herceptin treatment, surgery remained an independent factor associated with improved survival(HR 0.547[95%CI 0.359-0.971] p=0.001).Discussion: Surgical resection of the primary tumor in stage IV breast cancer patient was independently associated with improved survival, even after adjustment for other factors associated with survival. Randomized prospective trials are needed to validate these findings.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3117.
Does Having Primary Breast Reconstruction Influence Chest-Wall Radiotherapy Rates?
Authors: Agusti A. , Rusby J. , Sundaramorthy S. , Roche N. , Gui G. , Harris P. , James S. , Ross G. , MacNeill F. 
Published: December 2010

Abstract
BACKGROUND: Immediate breast reconstuction should be discussed with all patient's who require mastectomy. The immediate recontruction may interfere with postmactectomy chest wall radiotherapy (RT) .The adverse impact of chest-wall radiotherapy on the reconstructed breast is widely reported. Predicting who will require chest-wall RT prior to surgery can be difficult, limited to the knowledge of full pathological staging and often only known after mastectomy. Does having primary reconstruction influence in chest-wall RT decision making? Are women who opt for primary reconstruction less likely to receive RT than those who choose no reconstruction?METHODS: From 1st Jan 2008 to 31st March 2009, we performed 430 mastectomies 226 were mastectomy only (M0), 204 were mastectomy with immediate reconstruction (MIR). Data were prospectively recorded on chest wall recurrence risk adjuvant chest wall radiotherapy, type of breast reconstruction (tissue expander, fixed volume implant, autologous reconstruction only and autologous reconstruction implant assisted).Chest-wall recurrence risk was calculated from pathology.RESULTS:Performed 430 mastectomies, 335 for invasive disease, 53 for DCIS, 6 for ALH/LCIS, 36 benign (for risk reduction or symmetry purposes).Two hundred and twenty-six (52%) were mastectomy only (M0), 204 (48%) were mastectomy with immediate reconstruction (MIR).Chest wall radiotherapy + MO vs. MIRTotal RT 130(30%), of which 88 (67%, 88/130) and 44 (33%, 44/130) were MO and MIR respectively. MOMO+RTMIRMIR+RTLow Risk (ASCO pN-ve/T&lt;50mm)42 (18%,42/226)4 (9%,4/42)44 (21%,44/204)2 (4%,2/44)Moderate Risk (SUPREMO pN+ (1-3) and/or pT2)89 (39%)31 (34%,31/89)59 (29%)23 (39%,23/59)High Risk (ASCO pT_&gt;50mm and/or pN+_&gt; 4)77 (32%)53 (73%,53/77)29 (14%)19(65%,19/29) RT and Type of Reconstruction: Of the 204 MIR, 85 (42%) were autologous and 119 (58%) implant based of which 16 autologous (18%,16/85) and 30 (25%,30/119 ) implants received RT.CONCLUSION:Chest wall RT rates are broadly comparable across the three risk groups for MIR and MO suggesting MIR doesn't influence decision making regarding RT.The number of high risk MIR was small (14%) suggesting successful preoperative selection.Slightly higher radiotherapy rate for implant based reconstruction may be explained by staged reconstruction.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3119.
Oncoplastic Surgery Using Laparoscopically Harvested Omental Flap: Results of 100 Patients.
Authors: Zaha H. 
Published: December 2010

Abstract
Background: Indication of breast-conservation treatment (BCT) has been increased due to various oncoplastic techniques. The latissimus dorsi flap is one of the most commonly used techniques for partial breast reconstruction. The disadvantage of this technique is the presence of donor-site morbidity and deformity. Laparoscopically harvested omental flap (LHOF) may compensate for these disadvantages associated with the donor-site. The aim of this study was to access the safety and the efficacy of this procedure.Methods: Oncoplastic surgery using LHOF was applied to 100 patients who underwent either BCT or nipple-sparing mastectomy (NSM) between April 2002 and March 2009. The patients who underwent BCT had a large loss of breast tissue (more than 30% of breast tissue), and LHOFs were applied for partial breast reconstruction. All of omental flaps was laparoscopically harvested. The pedicled flap was extracted via a small subcutaneous tunnel created from the xiphoid process, and filled the dead space of a breast. Free flap was withdrawn from a small incision in the lower abdominal wall. Then microanastomoses between right gastroepiploic vessels and thracodorsal vessels were performed. The patients were followed-up for complications and cosmetic results.Results: 65 cases of BCT and 35 cases of NSM were included. The omental flaps were successfully harvested in 99 cases without conversion to open surgery (99%). Median operative time for harvesting the omental flap was approximately 1 hour. Morbidity associated with laparoscopy occurred in 8 cases (8%), which were 5 partial graft necroses, 2 vascular injuries of the gastroepiploic artery and one incisional hernia. Morbidities not associated with laparoscopy occurred in 9 cases (9%), which were two postoperative hematoma, 3 wound infections and 4 others. Cosmetic results were almost satisfactory, with a soft breast that was natural in appearance. Postoperative radiotherapy did not change the cosmetic outcome. Donor-site scars were minimal like those of laparoscopic cholecystectomy. However, in 17 patients (17%), the amount of omentum was found to be inadequate when applied for reconstruction after NSM. In 19 patients (19%), minor deformity or asymmetry of the reconstructed breast had occurred because of postoperative infectious complications or volume lack.Conclusion: Although there is a limit of volume, LHOF is safe procedure with minimal donor-site morbidity and deformity, and attractive autologous flap for partial breast reconstruction.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3120.
Notch-1 Confers Resistance to ErbB-2 Targeted Inhibition by Regulating PTEN, p27, and IGF-1R.
Authors: Mehta K. , Meeke K. , Clementz A. , Albain K. , Osipo C. 
Published: December 2010

Abstract
Background: Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 30% of breast tumors. Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab or lapatinib. We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors of ErbB-2, trastuzumab or a tyrosine kinase inhibitor (Osipo et al., 2008. Oncogene). Furthermore, we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor. Overexpression of IGF-1R and/or downregulation of PTEN, and p27Kip1 have been shown to be very sensitive markers of trastuzumab resistance. Based on our results and what is known from the literature, we asked by what mechanism Notch-1 contributes to trastuzumab resistance and can a combination therapy prevent or reverse the resistant phenotype by using a pre-clinical in vivo model.Methods: Using a pcDNA3.1-NIC construct expressing activated Notch-1 and a Notch-1 siRNA, we either increased NIC levels in trastuzumab sensitive or downregulated Notch-1 in trastuzumab resistant BT474 cells, respectively and measured protein and mRNA expressions of PTEN, p27Kip1, and the IGF-1R. In addition, BT474 breast tumor xenografts were generated in athymic mice and randomized to vehicle, MRK-003 or Ly411,575 gamma-secretase inhibitor, trastuzumab, or trastuzumab plus a gamma-secretase inhibitor. Tumor size was measured up to 14 weeks with treatments and up to 12 weeks after stopping treatments.Results: The results showed that intracellular, active Notch-1 (ICN) increased mRNA and protein expression of the IGF-1R, while simultaneously decreased protein expressions of PTEN and p27Kip1 in ErbB-2 positive breast cancer cells sensitive to trastuzumab. Conversely, knockdown of Notch-1 by siRNA in resistant cells decreased IGF-1R, while increasing PTEN and p27Kip1. The xenograft studies demonstrated that combining a GSI with trastuzumab either completely prevented tumor recurrence (MRK-003 GSI) or significantly delayed tumor recurrence (Ly 411,575 GSI).Conclusions: Taken together, these results suggest that Notch-1 potentially contributes to trastuzumab resistance by upregulating the IGF-1R and downregulating PTEN and p27Kip1 in vitro. The benefit of inhibiting Notch activity using a GSI in combination with trastuzumab is prevention of resistance and tumor recurrence.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3123.
Potential Benefit of an Agonistic Anti IGFIR Antibody (scFv-Fc) as an Effective Breast Cancer Therapy.
Authors: Zhang X. , Yee D. 
Published: December 2010

Abstract
Multiple monoclonal antibodies targeting the type-1 insulin-like growth factor receptor (IGFIR) are currently in different phases of clinical trials. All the reported antibodies inhibit biochemical activation of IGFIR and block cell proliferation. In contrast, we have reported an agonistic anti-IGFIR antibody scFv-Fc that stimulates IGFIR and its downstream signaling of PI3K and MAPK pathways to promote cell proliferation in vitro. Like the purely antagonistic antibodies, our previous work has shown that scFv-Fc can down regulate IGFIR levels, partially inhibit xenograft growth of MCF-7 cells in athymic mice, and render MCF-7 cells refractory to the mitogenic effects of IGF-I after the initial wave of agonistic activity. MCF-7 cells maintained long term in scFv-Fc have low levels of IGFIR expression, yet the remaining receptor is activated and inhibited by an IGFIR tyrosine kinase inhibitor (TKI) AEW541. In this study, we have further explored the future potential of using this antibody as breast cancer therapy. The common characteristic effect of anti-IGFIR antibodies is to down regulate IGFIR. Since scFv-Fc can activate IGFIR signaling in a manner different than the natural ligand IGF-I, we examined if this antibody could render cells more sensitive to TKI. In MCF-7 cells, IC50 of the IGF1R tyrosine kinase inhibitor AEW541 was decreased 5 to 10 fold when cultured in scFv-Fc. ER negative MDA-MB-231 cells are insensitive to both inhibitory antibody (AVE1642) and TKI (AEW541) in the presence or absence of IGF-I, which may due to the very low levels of IGF1R that are weakly activated by IGF-I. MDA-MB-231 cells were not affected by AEW541 in monolayer growth assays. After chronic treatment of MDA-MB-231 with scFv-Fc for 2 months, AEW541 significantly inhibited monolayer cell growth by 30% in the presence or absence of IGF-I. We also examined the effect of scFv-Fc's effect on AEW541 inhibition of cell motility in MDA-MB-231 cells. Both acute and chronic treatment of scFv-Fc dramatically inhibited cell migration by 90%.Inhibitory antibodies AVE 1642 and MK 0646 had no effect on cell migration. Both IGF-I and excess amounts of AVE 1642/MK 0646 did not reverse scFv-Fc inhibition on cell migration, suggesting other cell signaling system may be involved. In MDA231-BO, a metastatic variant of MDA-MB-231, scFv-Fc had less inhibitory effect on basal cell migration, but in combination of AEW541 treatment, cell migration was significantly decreased by 70%. In conclusion, our data suggests an antibody with agonistic activity may have different properties than purely inhibitory antibodies. Specifically, initiating biochemical signaling followed by inhibition of tyrosine kinase activity and receptor downregulation may be a potent way to disrupt IGF mediated breast cancer cell biology.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3125.