bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-07-35: Dragonfly Effect or Ironic Paradox: Prognostic Implication of Postsurgical Drain in Breast Cancer Patients
Authors: Yin W , Lin Y , Shen Z , Shao Z-M , Lu J 
Published: August 2014

Abstract
Background: Surgical removal of primary breast cancer may result in subsequent alterations of host milieu. Massive clinical data have indicated that surgical extirpation favorably modifies the natural history for some patients, but it may also precipitate the metastatic outgrowth for others. Drainage fluid, harvested from a post-surgical wound, appears to be a physiological response to surgical trauma. However, few clinicians have recognized that the volume of wound drain might mirror the postoperative recurrence kinetics.
Methods: A total of 1439 patients were selected retrospectively from a large database of patients who underwent surgery between Jan 1, 2000 and Dec 31, 2002 in Fudan University Shanghai Cancer Center, Shanghai, China. The Spearman rank correlation analysis was conducted to evaluate the association between drainage volume of postoperative day 1 (POD1) and clinicopathological parameters, which included age at diagnosis, body weight at diagnosis, total number of excised axillary lymph nodes (ALNs), time to drainage volume less than 30ml (TTV30), total protein and albumin concentrations in serum. Survival curves were performed with Kaplan–Meier method and annual recurrence hazard was estimated by hazard function.
Results: Drainage volume of POD1 was positively correlated with age at diagnosis (Spearman's P &lt; 0.001), weight at diagnosis (P &lt;0 .001) and number of excised ALNs (P &lt;0 .001) and TTV30 (P &lt;0 .001), whereas it was inversely correlated with total protein concentration in serum (p = 0.028). We also observed that drainage volume of POD1 was significantly higher in patients with larger tumors (P &lt; 0.001) and ALNs involvement (P = 0.030).
In the univariate survival analysis, there was less recurrence and death in patients with lower drainage volume of POD1 (both p = 0.006). Cox proportional hazards regression analysis revealed that drainage volume of POD1 was an independent predictor of recurrence-free survival (RFS; p = 0.035) and overall survival (OS; p = 0.047). Additionally, triple negative patients with larger volume of POD1 seemed to have poorer RFS (log-rank p = 0.022; Cox model P &lt; 0.05) and OS (log-rank p = 0.015; Cox model P &lt; 0.05).
Conclusions: Our study suggests that postsurgical drainage volume was strongly correlated with prognosis in breast cancer patients. The aim of this study was not only to enlighten novel prognostic factors, but also to infer that some host related characteristics such as extent of reaction to surgery play very important roles in the growth of micro-metastases. Therefore, integration of both host and tumor related factors be more precise to predict relapse risk than current modalities such as the St Gallen criteria, Oncotype-21 and Mammaprint etc. Further research on the underlying mechanism of this phenomena may lead the way to new adjuvant treatment targets and strategies.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-35.
Abstract P6-07-42: Patients with Nipple-areola Paget's Disease and Underlying Invasive Breast Carcinoma had a Very Poor Survival: a Matched Cohort Study
Authors: Ling H , Xu X-L , Liu Z-B , Shao Z-M 
Published: August 2014

Abstract
Purpose: Nipple-areola Paget's disease together with invasive breast cancer is a rare kind of disease. This study is to investigate the characteristic and survival of it.
Patients: From 2001 to 2005, all patients diagnosed as nipple-areola Paget's disease with underlying invasive breast carcinoma in Fudan University Shanghai Cancer Center (FUSCC) were recruited in this study (PD group).
Patients diagnosed as invasive breast cancer without Paget's disease were recruited in control group for clinical and pathologic features comparison.
Since tumors in PD group expressed more high risk factors (see results), a matched study was done to investigate whether the poor survival of PD group was by nature or due to the overexpression of high risk factors. The matched group was derived from all the patients who received mastectomy for invasive breast cancer (with no Paget's disease) during 2001 to 2005 in FUSCC. The match was conducted according to four variables: dimension of tumor, lymph node status, hormone receptor status and Her2 status. After matching, patients were randomly selected in a 3:1 ratio to patients in PD group.
Results: 52 patients were recruited in PD group. 22 (42.3%) patients' primary symptom were nipple change, 25 (48.1%) patients' primary symptom were mass in breast. Physical examination found no nipple-areola change in 24 patients at diagnosis, their Paget's disease were found unexpectedly by routine nipple-areola section examination after mastectomy.
More than 8000 invasive breast cancers were diagnosed during 2001 to 2005. 700 patients (140 consecutive patients per year, average monthly patient amount) were recruited in control group. Compared with control group, tumors in PD group had larger size, more axillary lymph node involvement, lower hormone receptor expression, higher HER2 expression and worse survival.

156 patients were recruited in the matched group. The 5-year relapse-free survival and overall survival were both lower for patients in PD group than those in the matched group (table1).
Conclusions: Patients with invasive breast cancer and Paget's disease tended to have larger size, more lymph nodes involvement, lower hormone receptor expression, higher HER2 expression and worse survival than those without PD. The matched study confirmed the survival disadvantage of patients with Paget's disease and underlying invasive breast cancer. Thus, oncologists should regard such patients as having high risk for relapse. Pathologists should exam the nipple-areola section carefully after mastectomy although the patient has no macroscopic nipple-areola change.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-42.
Abstract P6-08-10: Cancer as self: a novel assessment of patient identity as it relates to a cancer diagnosis
Authors: Horst KC , Fero KE , Haimovitz K , Dweck CS 
Published: August 2014

Abstract
Introduction: Previous studies have demonstrated that an individual's attitude towards self may impact how one faces challenges. Those who view themselves as malleable (growth mindset) approach challenges and problems as a learning opportunity and an opportunity to improve and change. In contrast, those who are more fixed in their approach (fixed mindset) have difficulty with challenges or setbacks. In the present study, we applied this conceptual framework to a cohort of breast cancer patients to evaluate their attitudes towards the cancer diagnosis. The goal of this study is to test the internal validity of this questionnaire and to correlate its findings with patient-reported measures of depression, anxiety and insomnia.
Methods: Twenty consecutive breast cancer patients undergoing radiation therapy completed an electronic survey consisting of 4 scales: the Hospital Anxiety and Depression Scale (HADS; 14 items), the Insomnia Severity Index (ISI; 7 items), a validated psychological questionnaire assessing fixed versus growth mindset (8 items), and an experimental questionnaire evaluating whether the patient views their disease as self-defining. Demographic and clinical variables were also collected. A principal components factor (PCF) analysis was used to examine the internal structure of the new questionnaire. Hierarchical linear regression analyses were performed to assess its relationship to other variables.
Results: Twenty patients completed the survey during the first week of radiotherapy. Median age was 57 (range, 31–81). Five patients (25%) had Stage 0 disease, 9 (45%) Stage I, 0 (0%) Stage II, 5 (25%) Stage III, and 1 (5%) Stage IV. Seven patients (35%) received chemotherapy while 13 (65%) did not. Eleven patients (55%) had significant others while undergoing treatment and 9 (45%) were single. The PCF analysis confirmed that the items of the experimental questionnaire were internally consistent (α = .88), such that all were retained in the final scale for subsequent analyses. The extent to which patients saw cancer as self defining was statistically significantly associated with their reported levels of depression (r = .60, p &lt; .005) and anxiety (r = .60, p &lt; .005). There was a similar trend with reported levels of insomnia which was not statistically significant (p = 0.2). Of the demographic and clinical variables, only stage of cancer was associated with depression and anxiety.
Conclusions: Patients undergoing treatment for breast cancer who view the cancer diagnosis as self-defining are more likely to self-report depression, anxiety, and insomnia. In this cohort, the experimental questionnaire demonstrated strong internal validity. An intervention that alters patients' perception of identity as it relates to the cancer diagnosis could be a promising compliment to the standard treatment of depression, anxiety, and insomnia.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-10.
Abstract P6-10-03: The PKC inhibitor PKC412 antagonizes breast cancer cell growth and enhances tamoxifen sensitivity
Authors: Shou J , Chew SA , Mitsiades N , Kumar V , Fu X , Chamness G , Osborne K , Schiff R 
Published: August 2014

Abstract
Background: AIB1 (SRC-3, NCoA3), a member of the p160/steroid receptor coactivators family, plays a critical role in cell growth and proliferation. In estrogen receptor-alpha positive (ER+) breast cancer (BC) cells, it coactivates estrogen- and additional transcription factors-dependent gene transcription, reducing the antagonistic activity of tamoxifen and resulting in tamoxifen resistance (TR). We have previously shown that BC patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen therapy, suggesting that AIB1 may be an important diagnostic and therapeutic target. Our findings that knocking down AIB1 attenuates ER signaling and inhibits breast cancer cell growth further indicate that the manipulation of AIB1 level could be an approach to treating BC and overcoming TR. Recently, it has been shown that protein kinase C (PKC) isoforms phosphorylate AIB1 and prevent its proteasome-mediated degradation. The present study was carried out to test if the multi-targeted kinase and PKC inhibitor PKC412 (midostaurin) is capable of promoting degradation of AIB1, inhibiting BC cell growth, and promoting tamoxifen antagonistic activity.
Methods: The ER+ MCF7, T47D, and ZR75-B BC cells and their tamoxifen-resistant derivatives (TR) were used. The Methylene Blue assay was employed to measure cell viability of BC cell lines after treatment with PKC412 or the combination of PKC412 with tamoxifen. To determine the impact of PKC412 on AIB1 and ER proteins and mRNA levels, we used immunoblotting and RT-qPCR, respectively.
Results: PKC412 successfully inhibited the growth of MCF7, T47D, and ZR75-B cells, and their tamoxifen-resistant derivatives. Treatment with PKC412 depleted AIB1 protein and reduced the level of ER protein without significant alteration in AIB1 mRNA level. Consequently, ER signaling was disrupted, as reflected by decreased expression of ER target genes such as GREB1. PKC412 also enhanced tamoxifen's antagonistic activity in the parental cell lines and sensitized tamoxifen-resistant MCF7 and ZR75-B cells to tamoxifen.
Conclusions: The results of this study suggest that the multi-targeted kinase and PKC inhibitor PKC412 can post-translationally destabilize AIB1 protein and ER, inhibiting BC cell growth and viability. PKC412 enhances tamoxifen's antagonistic activity on BC growth; furthermore, it sensitizes tamoxifen-resistant cells to tamoxifen. Thus, PKC412 is a promising agent to treat BC and, in combination with tamoxifen, to delay or overcome TR.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-03.
Abstract P6-11-02: Inhibition of mTOR and Fatty Acid Synthase (FASN) overcome acquired resistance to Trastuzumab, Lapatinib and both in HER2+ breast cancer
Authors: Puig T , Blancafort A , Giro A , Viqueira A , Viñas G , Massaguer A , Carrion-Salip D , Bolos MV , Urruticoechea A , Oliveras G 
Published: August 2014

Abstract
Introduction: Resistance to dual biological blockade of HER2 positive breast cancer arises as a novel therapeutic challenge with high clinical relevance. We have shown that inhibition of fatty acid synthase (FASN) has anticancer activity and enhances the effect of chemotherapy and anti-HER2 drugs in pre-clinical breast cancer models. Furthermore, our group has recently observed that inhibition of FASN can reverse resistance to anti-HER2 therapies.
The development of FASN inhibitors has consequently appeared as a novel anti-target modality for treating cancer. However, the clinical use of FASN inhibitors, such as Cerulenin, C75 and Epigallocatechin 3-gallate (EGCG) is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. We synthesized novel EGCG-related inhibitors to improve their use as anti-tumor agents. Within these, G28UCM was selected for its inhibitory effect of FASN activity and selective cytotoxicity in tumor cells.
Recently, it has been reported that mTOR blockade acts synergistically with HER2 inhibition to induce cell death and tumor regression in resistant breast cancer models.
Materials and Methods: We have developed long term HER2+/ FASN+ breast cancer cell lines (SKBr3) resistant to the HER2-monoclonal antibody Trastuzumab (SKTR), the EGFR/HER2-tyrosine kinase inhibitor Lapatinib (SKLR) or both (SKLTR). Once established, we have characterized these cells by studying a panel of EGF receptors signaling proteins with western blot analysis, changes in adherence to extracellular matrix proteins and invasion capacity with colorimetric assays. Using MTT assay, we have assessed the effect of the mTOR-inhibitor, Temsirolimus, and G28UCM on viability of parental and resistant cells. The isobologram method has been used to estimate the possible synergistic effect between both treatments.
Results: Resistant cells maintained downstream HER2 pathway activation by stimulating the expression/activation of alternative EGF family receptors and/or those specific ligands. Moreover, these cells increased adherence to extracellular matrix proteins and invasion capacity.
Different combination regiment of Temsirolimus with G28UCM displayed a strong synergistic effect in inducing cell death of both, parental and resistant HER2+ breast cancer cells.

Conclusions: The inhibition of mTOR and FASN is a potential novel therapeutic strategy in dual resistant HER2 positive breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-02.
Abstract P6-11-06: A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP) antagonist, in combination with weekly paclitaxel in patients with advanced solid tumors
Authors: Dienstmann R , Vidal L , Dees EC , Chia S , Mayer EL , Porter D , Baney T , Dhuria S , Sen SK , Firestone B , Papoutsakis D , Cameron S , Infante JR 
Published: August 2014

Abstract
Background: Impaired apoptosis is a common feature of cancer cells and may contribute to chemoresistance. LCL161 is an oral small molecule antagonist of Inhibitor of Apoptosis Proteins (IAPs) that sensitizes a subset of tumors from diverse lineages to treatment with cytotoxic therapies, including paclitaxel. Multiple breast cancer models are sensitive to LCL161 as a single agent and LCL161 acts synergistically with paclitaxel in these models. A phase I study established an LCL161 dose of 1800 mg once weekly as well tolerated, with strong evidence of pharmacodynamic activity at doses ≥320 mg. This ongoing phase Ib study defines the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of LCL161 in combination with weekly paclitaxel.
Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week followed by escalating doses of LCL161 administered once weekly immediately following paclitaxel. PK and biomarker sampling was performed.
Results: Thirty-two patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 4), and 1800 mg (n = 20). The most frequent adverse events considered LCL161-related included diarrhea (n = 11; 1 Grade 3), nausea (n = 8), fatigue (n = 7; 2 Grade 3), peripheral neuropathy (n = 6; 1 Grade 3), vomiting (n = 6), decreased appetite (n = 5), alopecia (n = 4), and anemia (n = 4). The principal DLTs were neutropenia, fatigue, and neuropathy. Significant cytokine release syndrome, the DLT of single-agent LCL161, has not been observed likely due to the use of dexamethasone as a premedication. No PK interaction between LCL161 and paclitaxel was observed. RECIST partial responses have been observed in 4 patients with diverse tumor types, including breast cancer. Preliminary antitumor activity in the expansion cohort with breast cancer patients will be presented.
Discussion: LCL161 and paclitaxel combination therapy is well tolerated, with manageable toxicities and no evidence of a PK interaction that might interfere with the activity of either agent. Enrollment of additional patients with breast and ovarian cancer into an expansion cohort is ongoing, utilizing an approach to identify those more likely to respond to treatment with IAP antagonists.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-06.
Abstract P6-13-02: Overcoming therapy resistance of metastatic breast cancer by enhanced tumor delivery of polymeric doxorubicin
Authors: Shen H , Xu R , Mai J , Huang Y , Ferrari M 
Published: August 2014

Abstract
Metastatic breast cancers are treated with chemotherapy drugs in clinic. However, patients usually develop therapy resistance quickly due to intrinsic and acquired mechanisms. Poor drug delivery to tumor cells may also contribute to therapy resistance. To address both biological and mass transport barriers to effective therapy, we developed a new doxorubicin-based formulation, polymeric doxorubicin (pDox), to be delivered using a porous silicon drug carrier, the multistage vector (MSV). We show the novel, rationally designed MSV/pDox drug enriches in tumor tissues and has considerable therapeutic efficacy in two animal models of triple negative breast cancer lung metastasis, conferring a significant survival advantage to animals treated with MSV/pDox over all other control groups (80% survival for the MSV/pDox group at 24 weeks post treatment vs. 0% survival for all others, log-rank test, p &lt; 0.001). Mechanistically, pDox is released from the MSV as nanoparticles by controlled, sustained kinetics, and enters tumor cells by vesicular transport. The active doxorubicin is released in the acidic environment in lysosomes, exits vesicles in the perinuclear region, and enters the nucleus for drug action. This effective mass transport mechanism kills both the bulk and therapy resistant cells, but avoids cardiac damage. As a result, this new nanodrug has a significantly higher therapeutic window over doxorubicin and Doxil.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-02.
Abstract PD01-03: Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment
Authors: Beelen KJ , Opdam M , Severson TM , Koornstra RHT , Vincent A , Wesseling J , Muris JJ , Berns EMJJ , Vermorken JB , van Diest PJ , Linn SC 
Published: August 2014

Abstract
BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients.
METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1–3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interaction between these markers and treatment.
RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12–0.47, p &lt; 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48–2.21, p = 0.95), p for interaction 0.003.
CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-03.
Abstract PD02-02: The effect of HER2 expression on luminal A breast tumors
Authors: Ellsworth RE , Valente AL , Shriver CD 
Published: August 2014

Abstract
Background: Luminal A (LumA) tumors are the most common subtype of breast cancer and have been associated with favorable prognosis. Although tumors can be considered LumA if they have &gt;1% expression of ER, negative HER2 status ranges from 0+ (no expression) to 2+ (weak to moderate expression in &gt;10% of cells) without concurrent genomic amplification. It is not clear how moderate levels of HER2 expression influence tumor biology in LumA tumors.
Methods: The Clinical Breast Care Project database was queried to identify all hormone receptor positive cases with HER2 status defined as 0+ (n = 89) or 2+/not amplified (n = 154). Clinicopathological characteristics were compared between groups using chi-square analysis. Twenty-five 0+ and 25 2+ tumors were subjected to laser microdissection and hybridized to U133 2.0 microarrays (Affymetrix). Gene expression data was analyzed using Partek Genomics Suite.
Results: Age at diagnosis did not differ between patients with no (58.5 years) or moderate (59.3 years) HER2 expression. Patient groups did not differ by ethnicity, tumor stage, grade or size, or lymph node status. Although breast cancer mortality was low, all patients who died of disease (n = 7) had moderate levels of HER2 expression (p = 0.016). At the molecular level, four genes were differentially expressed (p &lt; 0.01, &gt;2x-fold change): ESRRG expressed at significantly higher levels and DHRS2, SCUBE2 and SERPINA6 expressed at significantly lower levels in tumors with moderate HER2 expression.
Discussion: LumA (2+) tumors are dissimilar from LumA (0+) tumors. Increased expression of ESRRG has been associated with increased cellular proliferation and tamoxifen resistance, while decreased expression of SCUBE2 and SERPINA6 have been associated with inhibition of growth and proliferation. Together, these molecular differences suggest that LumA tumors with moderate HER2 expression, although classified as HER2 negative, have more aggressive characteristics than those without HER2 expression which may contribute to the significantly higher mortality rate seen in patients with LumA tumors expressing HER2.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-02.