bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-12-06: The Role of MAPK and PI3K/AKT/mTOR Signaling in Innate Lapatinib Resistance.
Authors: McDermott M , O'Brien N , McDonald K , Crown J , O'Donovan N , Slamon D 
Published: June 2012

Abstract
Background: Lapatinib is a tyrosine kinase inhibitor which blocks downstream MAPK and P13K/AKT/mTOR proliferation and survival signaling pathways in HER2 positive breast cancer cell lines, tumor xenografts and HER2 positive breast cancer patients. However, pre-clinical and clinical studies have shown that not all HER2 positive patients respond to lapatinib and thus innate resistance to lapatinib exists. The identification of biomarkers of lapatinib response is therefore critical and would enable individual therapeutic decisions to be based on tumor biology rather than basic histopathology data alone. The aim of this study was to examine the role of MAPK and PI3K/AKT/mTOR signaling in a panel of lapatinib sensitive and resistant HER2−amplified breast cancer cell lines to identify pharmacodynamic markers of response to lapatinib treatment.
Methods: Dose response curves were generated to determine sensitivity to lapatinib in a panel of 17 HER2−amplified breast cancer cell lines. Total and phosphorylated levels of HER2, HER3, EGFR, AKT, ERK, S6K and eEF2 were determined following 24 hours lapatinib treatment in each of the cell lines.
Results: Twelve of the cell lines were sensitive to lapatinib with IC50g &lt; 1 μM while 5 of the cell lines were innately resistant to lapatinib with IC50g &gt; 1 μM. Levels of pHER2 and pHER3 were decreased in response to lapatinib in all cell lines independent of sensitivity to lapatinib. This suggests that inhibition of HER2/HER3 activation is not indicative of response to lapatinib treatment. There was also no correlation between the levels of HER2, HER3, and EGFR and sensitivity to lapatinib in the cell line panel.
In lapatinib sensitive cell lines, lapatinib decreased PI3K (pAKT), mTOR (pS6K) and MAPK (pERK) signaling and increased peEF2 levels. In contrast the levels of pAKT, pS6K, peEF2 and pERK were maintained following lapatinib treatment in lapatinib resistant cells. The continued activation of these proteins in the presence of lapatinib suggests a possible feedback mechanism that warrants further investigation. These data confirm that maintained signaling through either the P13K/AKT/mTOR pathway or the MAPK pathways in the presence of lapatinib can be an early pharmacodynamic biomarker of response.
Conclusions: Maintenance of pAKT, pS6K, peEF2 and pERK levels, in response to lapatinib treatment correlates with lapatinib resistance. These data suggest that alterations in the P13K/AKT/mTOR and MAPK pathways play an important role in innate lapatinib resistance and pharmacologically targeting these pathways is a rational therapeutic approach for overcoming innate lapatinib resistance.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-06.
P1-12-18: Change in HER2 Status in HER2 Positive Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without Anti-HER2 Therapy: Analysis of Two Consecutive Cohorts.
Authors: Barbieri E , Piacentini F , Dieci MV , Ficarra G , Bettelli S , Conte P , Guarneri V 
Published: June 2012

Abstract
Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon. Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents.
Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib).
HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples.
Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2).
Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018).
Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-18.
P1-12-25: Evaluation of PTEN, EGFR and Ki67 Expression as Predictors of Response to a Trastuzumab-Containing Neoadjuvant Chemotherapy Regimen in a HER-2 Over-Expressing Locally Advanced Breast Cancer (LABC) Trial.
Authors: Ho J , Turashvili G , Hayes M , Gelmon KA , Ellard SL , Macpherson N , Pansegrau G , Chia SK 
Published: June 2012

Abstract
Background: In patients with HER-2 over-expressing breast cancer, predictors of trastuzumab response and resistance remain unclear and unvalidated. In an exploratory analysis within a phase II trial, we evaluated various biologic markers as predictors of response or resistance to a trastuzumab containing neoadjuvant chemotherapy regimen.
Methods: A tissue microarray (TMA) was constructed from formalin-fixed paraffin-embedded tumor tissue samples obtained prior to neoadjuvant chemotherapy in 21 (from a total of 30) HER-2 positive stage II-III patients. Protocol treatment consisted of 4 cycles of 5-Fluorouracil, Epirubicin and Cyclophosphamide (FEC100) followed by 4 cycles of Docetaxel, Carboplatin (AUC 6) and Trastuzumab (TCH). Immunohistochemical (IHC) analyses of estrogen receptor (ER), progesterone receptor (PR), HER-2, Ki67, EGFR and PTEN were performed utilizing previously published protocols and cut-offs. HER-2 equivocal (2+) by IHC cases was confirmed by prior FISH analysis. Fisher's exact test was used for statistical analysis.
Results: 21 patients had sufficient tumour for analysis. Median age at diagnosis was 49 years old, 67% were pre-menopausal, and biomarker expression was as follows: 43% ER positive, 29% PR positive, and 100% HER-2 positive. 14 patients (67%) had pathologic complete response (pCR) following the completion of neoadjuvant chemotherapy and trastuzumab. In general, tumour samples showed high Ki67 (&gt;14%) staining (62%), low EGFR positivity (14%), and high PTEN expression (71%). Neither high Ki67 expression (p=0.65), any EGFR expression (p=0.26), nor PTEN loss (p=0.60) was associated with higher or lower rates of pCR respectively.
Conclusion: In our small cohort of locally advanced HER-2 over-expressing tumours, baseline expression of Ki67, EGFR and PTEN were not associated with pCR to a neoadjuvant sequential anthracycline and taxane/trastuzumab combination regimen. Additional biomarkers for an activated PI3K pathway and for p95 will be attempted.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-25.
P1-14-05: Surgical Complications from the GeparQuinto Trial of Patients Receiving Preoperative Bevacizumab.
Authors: Eidtmann H , Kittel K , Rezai M , Tesch H , Ulmer HU , Stirnberg S , Belau A , Mau C , Stickeler E , Schrader I , Fasching P , Salat CT , Abdallah A , Holms F , Schwedler K , Nekljudova V , Loibl S , von Minckwitz G 
Published: June 2012

Abstract
Background: Bevacizumab has been reported to increase the risk of surgical complications, especially in pts treated with neoadjuvant chemotherapy.
Methods: In January 2010 it was decided to collect surgical complications prospectively on a specifically developed from. All patients received chemotherapy with epirubicin/cyclophosphamide (EC) followed by docetaxel (T) with or w/o bevacizumab. Patients not responding to the first 4 cycles of EC+/−B were enrolled in another setting. All patients receiving bevacizumab were supposed to be operated at 5 weeks after the last infusion of bevacizumab.
Results: Data from 699 patients have been prospectively collected, 329 received EC-T and 370 ECB-TB. Median age was 48 years in both arms. Median tumor size was 30mm in the ET-C arm vs 35mm in the ECB-TB arm (p=0.13). Multifocal or multicentric disease was present in 21% in the EC-T arm vs 22.4% (p=0.74). 36% of the patients received a sentinel node biopsy prior to start of neoadjuvant chemotherapy in both groups. 68.7% of patients received breast conserving therapy in the EC-T arm compared to 71.1% in the ECB-TB arm (p=0.54). The rate of pathological complete response was 19.5% with EC-T compared to 23.2% with ECB-TB (p=0.26). The median time from last CHT+/− bevacizumab to surgery was 29 days in EC-T and 34 days in ECB-TB. Bleeding or hematoma were reported in 6.7% of the patients treated by EC-T and 7.1% with ECB-TB (p=0.88). Wound infections or abscess were reported in 2.5% with EC-T and 3.9% with ECB-TB (p=0.39). Delayed wound healing was reported in 3.4% with EC-T and 6.3% with ECB-TB (p=0.11). Necrosis was reported in 1.9% with EC-T and 2.5% with ECB-TB (p=0.80). Any complication was reported in 11% with EC-T compared to 15.3% with ECB-TB (p=0.12).
Conclusion: In general the rate of surgical complications was low. Patients treated with bevacizumab had a numerical increase of surgical complications. However, none of the differences were statistically significant. The intervals from last infusion to surgery as defined by the study protocol appear to be safe.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-05.
P1-17-09: A Phase 1/2 Dose-Escalation Study of SAR245408 (S08) or SAR245409 (S09) in Combination with Letrozole (L) in Subjects with Hormone Receptor-Positive and HER2−Negative (HR+/HER2−) Breast Cancer (BC) Refractory to a Nonsteroidal Aromatase Inhibitor (AI).
Authors: Baselga J , Tolaney S , Hart L , Gomez P , Gartner E , DeCillis A , Ruiz-Soto R , Lager J , Burris H 
Published: June 2012

Abstract
Background: Upregulation of PI3K activity is a common molecular mechanism involved in resistance to AIs. S08 is a potent, orally bioavailable, pan-PI3K inhibitor. S09 is a potent, orally bioavailable inhibitor of PI3K which also possesses mTOR inhibitory activity. Both compounds exhibit robust PI3K and ERK pathway inhibition in paired human tumor biopsy samples from phase 1 studies (Edelman G, et al. ASCO 2010; Brana I, et al. ASCO 2010).
Methods: This ongoing, open-label, multicenter, phase 1/2 study (NCT01082068) was designed to evaluate the safety and tolerability of L in combination with either S08 (Arm 1) or S09 (Arm 2). Eligible female patients (pts) were ≥18 yrs, ECOG PS 0–1, with advanced or recurrent HR+/HER2− BC whose disease is refractory to nonsteroidal AIs. Phase 1 used an ascending 3+3 dose-escalation design and pts were accrued to each arm until no more than 1/3 pts or ≥33% of 3–6 pts at a given dose level experienced a dose-limiting toxicity (DLT) during the first 28-day cycle. Pts were alternately assigned to Arm 1 or Arm 2 and received 2.5 mg L PO (qd) in combination with different dose levels of either S08 (Arm 1; starting dose 200 mg tablets, PO, qd) or S09 (Arm 2; starting dose of 30 mg capsules, PO, bid). After reaching a preliminary maximum tolerated dose (MTD) for each combination, pts will accrue to the phase 2 portion of the study. A two-stage design will be used evaluate the phase 2 co-primary endpoints of ORR and PFS. Each arm will be evaluated independently and no formal comparisons between arms are planned.
Results: As of June 1st 2011, 17 pts were enrolled to Arm 1 (8 pts) or Arm 2 (9 pts). Median age was 54 yrs. Based on preliminary data, the adverse event profile in both arms were similar to those reported in the single agent phase I studies for S08 and S09 respectively. SAEs reported in Arm 1 (2 subjects) included 2 cases of Gr1 pneumothorax and 1 Gr4 pneumonitis; in Arm 2 (2 subjects) included Gr4 lumbar pain and Gr4 elevation of ALT and AST. No DLTs were reported in Arm 1 while one DLT (Gr3 skin rash) was reported in Arm 2 at a dose level of S09 50 mg bid (table 1). Arm 1 dosing data from S08 400 mg qd + L 2.5 mg qd dose level (maximum dose level allowed per protocol) will be completed by August 2011. For Arm 2, the MTD was S09 50 mg bid + L 2.5 mg, qd.

Discussion. Both S08 and S09 can be combined with L, and maximal doses for both combinations were established. Additional safety, PK and efficacy data will be presented from phase 1.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-09.
P2-01-11: Fish Oil Targets miR-21 To Increase PTEN Expression for Inhibition of Bone Metastatic CSF-1 in Breast Cancer Cells.
Authors: Mandal CC , Ghosh-Choudhury T , Ghosh Choudhury G , Ghosh-Choudhury N 
Published: June 2012

Abstract
Current therapy for the breast cancer patients is aimed at treating the cancer mainly at the primary site with limited ability to block metastasis. We have recently shown that fish oil (FO) diet significantly prevents MDA MB-231 breast cancer cell (MDA) metastasis to bone in a mouse model. Colony stimulating factor-1 (CSF-1) is one of major osteoclastogenic cytokines responsible for osteolytic metastasis of breast cancer. Quantitative RT-PCR (qRT-PCR) analysis showed significant inhibition of CSF-1 mRNA expression in fish oil fed mice xenograft tumor samples and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two ω-3 fatty acids in fish oil, inhibited CSF-1 mRNA and protein expression in MDA cells. A positive correlation was observed between expression of CSF-1 and the bone metastatic potential of different breast cancer cells. We have demonstrated recently upregulation in PTEN expression by FO diet as a mechanism of breast tumor growth arrest in mice. Over expression of PTEN inhibited migration of MDA cells. PTEN is a negative regulator of PI 3 kinase/Akt signaling. We investigated the mechanism of CSF-1 expression by breast cancer cells. Cotransfection of the CSF-1 promoter-driven luciferase plasmid (CSF-1-Luc) in MDA with PTEN or dominant negative (DN) PI 3 kinase or DN Akt, inhibited the transcription of CSF-1, indicating requirement of PI 3 kinase/Akt signaling. Several oncogenic microRNAs including miR-21 have been shown to induce metastasis of cancer cells. Fish oil fed mice tumors and DHA- and EPA-treated MDA cells significantly blocked miR-21 expression in MDA. PTEN mRNA 3'UTR contains miR-21 recognition element. Over expression of miR-21 inhibited PTEN 3'UTR-Luc reporter activity but it was increased by downregulation of miR-21, indicating functional targeting of PTEN mRNA by miR-21 in MDA. Similarly, expression of either miR-21 or miR-21 Sponge (plasmid-coded anti-miR-21 sequences) in MDA significantly suppressed or increased PTEN protein, respectively. Moreover, DHA-increased PTEN expression is reversed by over expression of miR-21 indicating a critical regulation of PTEN by miR-21. miR-21 over expression increased migration of MDA cells and partially reversed DHA- or EPA-mediated inhibition of migration. Since PTEN regulates expression of CSF-1, we examined the involvement of miR-21. Expression of miR-21 enhanced while miR-21 Sponge reduced expression of CSF-1 mRNA and its transcription. Furthermore, DHA-inhibited CSF-1 mRNA expression is reversed by over expression of miR-21. Together these results uncover a novel function of fish oil, which beheads miR-21 signaling to dampen expression of CSF-1 thus preventing osteoclastogenesis and osteolytic lesions in breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-11.
P2-01-15: RT-PCR Gene Profiling for the Prediction of Bone Metastases in Primary Breast Cancer.
Authors: Ibrahim T , Mercatali L , Ricci R , Scarpi E , Liverani C , Serra L , Guerra D , Ciani S , Amadori D 
Published: June 2012

Abstract
Background: Patients with breast cancer frequently develop bone metastases, which are responsible for high morbidity and mortality. It is known that numerous molecules are involved in the bone metastasization process and that only cancer cells with a specific molecular profile are capable of reaching and colonizing bone tissue. The early detection of patients with a high probability of relapsing to bone could be used to select candidates for tailored therapy with bone-specific drugs such as bisphosphonates or RANK-L inhibitors. The aim of the present study was to identify a pattern of tissue markers from primary breast cancer capable of predicting bone metastatization.
Material and methods: The expression of different markers was retrospectively analyzed in frozen breast cancer tissue samples from 40 patients comprising 15 cases with no evidence of disease (NEDP), 15 with bone metastases (BMP), and 10 with visceral metastases (VMP). Twelve transcripts were analyzed by Quantitative Real time PCR: trefoil factor 1(TFF1), DKK1, bone sialoprotein (IBSP), heparanase (HPSE), osteopontin (SPP1), Agr2, SPARC, CTGF, COMP, follistatin (FST), osteoprotegerin and RANK. The predictive accuracy of each marker was calculated using receiver operating characteristic (ROC) curves.
Results: Analysis of marker expression in the 3 different subgroups showed twofold higher median values of COMP and HPSE in BMP with respect to either NEDP or VMP (no significant difference). Furthermore, TFF1 median value was about sevenfold higher in BMP than in the other 2 subgroups (p=0.05). The area under the curve (AUC) was 0.73 for TFF1 and 0.62 for COMP and HPSE. Considering markers as dichotomous variables, TFF1 expression in BMP reached 67% compared to 21% and 20% in NEDP and VMP, respectively. In dichotomous variable analysis, the most important result was observed for TFF1; in particular, TFF1 positivity was observed in 67% of cases in the BMP subgroup compared to only 21% and 20% in NEDP and VMP, respectively. The combination analysis of TFF1 and other markers showed that positivity to at least one of the three markers, TFF1, DKK1, or IBSP, was observed in 80% of cases for the BMP group, and in only in 21% and 20% of cases in NEDP and VMP subgroups (p=0.041). Another interesting marker was RANK: although sensitivity was fairly low (12%), specificity reached 100% in both control groups.
Conclusions: Our preliminary study identified a RT-PCR gene expression pattern in primary breast cancer that could predict patients destined to bone relapse. Such patients could consequently benefit from adjuvant treatment with bone-targeted therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-15.
P2-01-16: Dissecting the Cellular Mechanism of Induction and Sustenance of Dormancy by Rho GTPases in Breast Cancer.
Authors: Chatterjee M , van Golen KL 
Published: June 2012

Abstract
Tumor dormancy has been a very real problem in breast cancer survivors where recurrences are common and usually fatal. Molecular mechanisms involved in this process are often poorly understood and are a hot spotin breast cancer research today.
We have found that Rho GTPases, specifically RhoC, is hyperactivated in low metastatic dormant breast tumor cells while RhoA is downregulated. We also found RhoC causes phosphorylation of c-jun NH2 terminal kinase (JNK) in these cells which in turn activates the process of autophagy, a possible mode of cell survival in dormant tumor cells. Modulating RhoC affected phosphorylation of JNK. Also, abrogating JNK by a pharmacological inhibitor SP600125 inhibited expression of the autophagy marker LC3B-II. Autophagy genes like Atg 5 and Atg 12 were expressed along with the autophagy marker LC3B-II. On inhibiting autophagy by a specific inhibitor 3-Methyladenine (3-MA), cells did not readily undergo apoptosis but on stressing them doubly with LY294002, an inhibitor of Class I PI3K, along with 3-MA (inhibitor of Class III PI3K), significant number of dormant cells underwent apoptosis as observed by TUNEL staining. We also found that p190RhoGAP was activated in these dormant cells which may lead to the observed downregulation of RhoA activation levels. Involvement of beta-1 integrin along with c-src in activation of RhoC was observed in these dormant cells. We are in the process of further elucidating these signal transduction processes that might be involved in cellular dormancy of breast cancer.
A better understanding of some of the cellular mechanisms of induction and sustenance of dormancy may aid in formulating therapies for annihilating these dormant tumor cells thus preventing the often fatal relapses in breast cancer survivors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-16.
P2-01-21: The Biological Influence of Brain Derived Neurotrophic Factor (BDNF) on the Aggressiveness of Human Breast Cancer Cells.
Authors: Yang MX , Martin TA , Jiang WG 
Published: June 2012

Abstract
Introduction: Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily and has been indicated in the pathophysiology of the nervous system and is important in a number of neurological and psychological conditions. Recently, BDNF has also been shown to play a role in the development and progression of solid tumours myeloma, lung cancer and prostate cancer. It has been recently reported that BDNF is also aberrantly expressed in human breast cancer and that a raised level of BDNF is associated with poor clinical outcome and reduced survival. The present study aimed to investigate the biological role of BDNF in human breast cancer. Materials and methods: A panel of human breast cancer cells were used in the present study. The expression profile of BDNF was evaluated using RT-PCR. We constructed a set of anti-BDNF transgenes which were used to transfect breast cancer cells in order to generate BDNF knockdown cells (MCFΔBDNF). The impact of BDNF knockdown on growth and cellular migration were evaluated using standard growth assays and ECIS (electronic cell impedance sensing) technology.
Results: BDNF gene transcripts were successfully detected in the breast cancer cell lines, MCF-7, MDA MB-231 and ZR 75-1. MCF-7 wild type cells were subject to transfection of anti-BDNF transgenes, followed by the establishment of BDNF knockdown sub-lines and empty vector control cells (MCFpef). Loss of BDNF in breast cancer cells resulted in reduction of cell growth rate (growth rate in MCFΔBDNF by day 3 1.60+/−0.11, compared with 2.06+/−0.04 in MCFpef, p=0.006). Using electric cell-substrate impedance sensing, it was found that loss of BDNF in breast cancer cells resulted in a significant increase in the rate of cellular attachment and migration (migration rate over 14 h in ohms: MCFΔBDNF 6310.125+/−595.183 compared with MCFpef 5115.5 +/−422.394, p=0.0003).
Conclusion: When BDNF was stably knocked down in MCF-7 cell lines, the growth and proliferation were decreased. The ECIS results also showed that cell migration was decreased in MCF-7 cells stably transfected with ribozymes for BDNF compared with the vector control. It is concluded that BDNF, a neurotrophic growth factor aberrantly expressed in cancers such as breast cancer, has a profound impact on the cellular behaviour of breast cancer cells and that loss of BDNF is associated with a reduction of the aggressiveness of breast cancer. BDNF is therefore a potential therapeutic target in breast cancer and its effect in human breast cancer requires further investigation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-21.