bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-04-11: Use of synthetic isoprenoids to target protein prenylation and Rho GTPases in breast cancer invasion
Authors: Chen M , Knifley T , Subramanian T , Spielmann HP , O'Connor KL 
Published: August 2014

Abstract
Tumor metastasis causes the majority of cancer deaths. Dysregulation of small GTPases such as K-Ras and Rho family GTPases (RhoA, RhoC, Rac1 and Cdc42) is critical to drive the invasion and metastasis of a variety of cancers including breast carcinomas. In order to fulfill their biological functions, these GTPases must properly localize subcellularly and associate with cellular membrane. The association of these proteins to membranes is regulated by a series of post-translational modifications including either farnesylation or geranylgeranylation of the C-terminal CaaX motif, thus providing the rationale to target the farnesyltransferase (FTase) and geranylgeranyltransferases (GGTase) as the potential anti-cancer drugs. However, FTase inhibitors (FTIs) failed in clinic due to alternative prenylation, which causes K-Ras to be geranylgeranylated, and their inability to target geranylgeranylated proteins such as Rho family GTPases. As an alternative, we have developed a unique class of potential anti-cancer therapeutics called Prenyl Function Inhibitors (PFIs), which are synthetic farnesol or geranylgeraniol analogs that act as alternative substrates for FTase or GGTase but do not support normal prenyl function. Here, we test the ability of our lead PFIs anilinogeraniol (AGOH; farnesol analog) and anilinofarnesol (AFOH; geranylgeraniol analog) to impact the migratory and invasive capacities of breast carcinoma cells. We found that AGOH treatment effectively decreased the invasion of MDA-MBA-231 in a two-dimensional invasion assay at 100 mM while it blocked invasive growth in three-dimensional (3D) culture model in as little as 20 μM. Notably, the effect of AGOH on 3D invasive growth was phenocopied by electroporation of cells with C3 exotransferase, which ribosylates and inactivates Rho proteins. The results demonstrate that Rho proteins are essential for the invasive growth of MDA-MB-231 cells. To determine how AGOH impacts Rho signaling, we performed RhoA and RhoC activity assays in MDA-MB-231 and MDA-MB-468 cells. We determined that AGOH blocked RhoA and RhoC activation in response to LPA and EGF stimulation. Notably, the geranylgeraniol analog AFOH was more potent than AGOH in inhibiting RhoA/C activation and invasive growth where it inhibited RhoA and RhoC activation completely at 20 μM and blocked the invasive growth of MDA-MB-231 cells at ≤ 5 μM. Interestingly, both AGOH and AFOH had no effect on the growth of MCF10A cells in 3D culture. Collectively, this study demonstrates that our lead PFI compounds dramatically inhibited breast cancer invasion, at least in part, through affecting RhoA and RhoC function; thus, suggesting that targeting the function of Rho prenylation by PFIs will offer a promising mechanism for the treatment of breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-11.
Abstract P6-05-03: Evaluation of predictive markers for clinical outcome after neoadjuvant radiochemotherapy in breast cancer
Authors: Matuschek C , Boelke E , Nestle-Krämling C , Speer V , Prisack H , Gerber PA , Bojar H , Audretsch W , Roth S , Budach W 
Published: August 2014

Abstract
BACKGROUND:
Neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) is an innovative method in treating patients. Proliferation markers make up the majority of genes included in RNA-based prognostic gene signatures applied for breast cancer patients. In this subgroup analysis long-term clinical outcome data and predictive factors were analyzed.
PATIENTS AND METHODS:
During 1991-1998, a total of 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or -in case of breast conservation- a 10-Gy interstitial boost with (192)Ir after loading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The impact of age, tumor grade, nodal status, hormone and growth factor receptor status (ER, PR, EGFR), p53, ki-67, HER2/neu, and bcl-2 on pathological complete response pCR and disease-free survival were examined in uni- and multivariate terms.
RESULTS:
Hormone receptor status, proliferative activity, bcl-2, EGFR-status and clinical tumor size had a significant impact on predicting neoadjuvant therapy success. Age, cN, grading, p53, and HER2/neu status failed to reach a significant correlation to complete remission. All examined immunohistochemical factors with the exception of EGFR, and all clinical factors displayed an univariately significant impact on DFS (disease free survival). Particularly, while HER-2/neu had no predictive value for pCR it displayed the highest impact on DFS after complete response (n = 92), even in a multivariate setting with clinical tumor size and nodal status. Complementary, p53 was the most superior immunhistochemical factor for prognosis after neoadjuvant incomplete remission (n = 223).
CONCLUSION:
Her2/neu is a predictive marker for overall survival independent from the pCR. It has no predictive value for the pCR. P53 is a prognostic marker for patients with incomplete remission. Prospective studies are needed to evaluate their use for decisions to further individualize adjuvant treatment after neoadjuvant radiochemotherapy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-03.
Abstract P6-05-08: Nuclear HER3 localisation plays a role in trastuzumab resistance in HER2-positive breast cancer
Authors: Hashimoto K , Roxanis I , Generali D , Andreis D , Strina C , Cappelletti M , Macaulay V , Kong A 
Published: August 2014

Abstract
Background: HER3 is known to locate in the nucleus. Unlike HER4, nuclear HER3 translocation has not been reported to be due to a proteolytic cleavage process by ADAM17 and gamma-secretase. The mechanisms of nuclear HER3 induction and its role in relation to trastuzumab treatment and resistance for HER2-positive breast cancer is unclear.
Methods: Using nuclear fractionation and confocal microscopy, nuclear HER3 localisation was investigated in response to trastuzumab with or without ADAM17 inhibitor and gamma-secretase inhibitor in a panel of HER2 expressing cell lines. We also correlated nuclear HER3 expression by immunohistochemistry with treatment response in patients who underwent window trastuzumab study as well as the survival outcome in a cohort of HER2-positive breast cancer patients using Kaplan–Meier survival curves with Log-rank test.
Results: HER3 ligand heregulin and trastuzumab was found to induce nuclear HER3 translocation in HER2-positive breast cancer cell lines, including SKBR3. Nuclear HER3 was also enriched in acquired trastuzumab resistant SKBR3 cells (SKBr3-TR). Trastuzumab treatment induced several HER3 fragments and HER3100kD was found to be responsible for nuclear HER3 enrichment by fractionation. This fragment was confirmed to be a specific band of HER3 as shown by HER3 knockdown. Nuclear HER3 was reduced by inhibiting either gamma-secretase or ADAM17 inhibitor. Gamma-secretase or ADAM17 inhibitor reduced HER3100kD in both SKBr3 and SKBr3-TR cells.
In HER2-positive breast cancer patients who underwent window trastuzumab study, baseline nuclear HER3 status was not a predictor of response for trastuzumab monotherapy at day 21. However, nuclear HER3 was enriched after trastuzumab treatment in a poor-responder patient. Total HER3 expression level in cytoplasm positively was correlated with poor response to trastuzumab monotherapy in HER2-positive patients (r = 0.67, p = 0.05). There was no statistically significant difference in disease-free survival between positive and negative nuclear HER3 expression but the number of patients was small (n = 87). Further validation to assess nuclear HER3 expression as a prognostic and predictive biomarker in HER2-positive breast cancer patients undergoing trastuzumab treatment will be assessed in randomized tumour samples from FinHER study.
Conclusion: Heregulin and trastuzumab treatment seems to induce nuclear HER3 translocation in some of the HER2 positive breast cancer cells. This may be due to proteolytic cleavage of HER3 as it is reduced by ADAM17 or gamma-secretase inhibitor. Enriched nuclear localisation of HER3 seems to be one possible mechanism of acquired resistance to trastuzumab in HER2-positive breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-08.
Abstract P6-06-16: Young age as a good prognostic factor in de novo metastatic breast cancer
Authors: Lee GE , Dawood S , Haaland BA , Tan PS , Bhoo-Pathy N , Dent RA 
Published: August 2014

Abstract
Background
While breast cancer is relatively rare in young women under the age of 40, its incidence is increasing and accounts for up to 40% of all female cancers. Young age at diagnosis is associated with a poorer prognosis in early breast cancers; however little is known about the natural history of young women with metastatic breast cancer. We aim to evaluate the effect of age on breast-cancer specific survival (BCS) and overall survival (OS) for patients with de novo metastatic breast cancer using data from the SEER registry.
Methods
We retrospectively analyzed 14155 patients with de novo metastatic breast cancer from the SEER registry between 2000 and 2009. Young women were defined as 50 years and below and further subdivided into three groups: 20-34, 35-39, and 40-49 years. Age 50-69 years served as a comparison group. Unadjusted overall survival (OS) and breast cancer specific survival (BCS) were accessed using Kaplan-Meier plots and compared across groups using log-rank tests. Cox proportional hazards models were then fitted to determine the association between survival end point and age after adjusting for patient and tumor characteristics.
Results
546 (3.9%) patients were age 20-34 years, 750 (5.3%) were 35-39 years, 3049 (21.5%) were 40-49 years and 9810 (69.3%) patients were 50-69 years. Median BCS among patients age 20-34, 35-39, 40-49 and 50-69 years was 30, 33, 35, 28 months respectively (P&lt;0.0001). Median BCS among patients with estrogen receptor positive disease who were age 20-34, 35-39, 40-49 and 50-69 years was 43, 42, 51, 37 months respectively (P&lt;0.0001). Similarly median BCS among patients with estrogen receptor negative disease who were age 20-34, 35-39, 40-49 and 50-69 years was 21, 18, 18, 17 months respectively (P&lt;0.0001). In the multivariable model compared to patients who were age 50 -69 years those aged 20-34 years (HR 0.88, 95% CI 0.78-0.99), 35-39 years (HR 0.82, 95% CI 0.74-0.91) and 40-49 years (HR 0.84, 95% CI 0.79-0.89) had a significantly decreased risk of death from breast cancer. Similar results were obtained for OS.
Conclusion
Younger patients defined by age less than 50 years had a better BCS and OS when compared against older age group in the setting of de novo metastatic breast cancer. This may be explained by lack of important comorbidities, relatively good performance status as well as ability to tolerate more lines of chemotherapies.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-16.
Abstract P6-06-24: Intact p53 can predict more hormonal therapy benefit in invasive breast cancer: Evaluation of interactions between immunohistochemical p53 status and adjuvant therapy
Authors: Lee JW , Kim HJ , Son BH , Ahn SH 
Published: August 2014

Abstract
Background: To confirm the prognostic and predictive values of p53 accumulation, particularly in invasive breast cancer patients sorted according to subgroup based on immunohistochemical hormone receptor (HR) and HER2 status.
Methods: A total of 15,598 immunohistochemical data for p53, ER, PgR, and HER2 were retrospectively retrieved from the web-based database of the Korean Breast Cancer Society. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated and compared with the Kaplan-Meier method with log-rank test. Multivariate analyses were performed using a stratified Cox proportional hazard regression model. A model evaluating interactions between p53 and both hormonal therapy and chemotherapy was used to determine the treatment benefit from both modalities.
Results: Prognostic value of p53 was most significant in the HR+/HER2- subgroup for OS and BCSS, with hazard ratios of 1.44 (95% CI, 1.08-1.93) and of 1.47 (95% CI, 1.09-1.99). The hazard ratios for p53 overexpression had borderline significance in the HR+/HER2+, and were invalid in the HR-/HER2+ and HR-/HER2- subgroups. The model with interaction terms revealed that hormonal therapy significantly interacts with p53 status (p = .002 and .007 for OS and BCSS), resulting in an insignificant prognostic value of p53 status (p = .268 and .296 for OS and BCSS). An interaction between chemotherapy and p53 status was not found in this model.
Conclusion: p53 overexpression has independent prognostic value, particularly in the HR+/HER2- invasive breast cancer, which is most likely caused by differential treatment benefits from hormonal therapy depending on p53 status.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-24.
Abstract P6-06-54: Analysis of treatment and survival of pathologic occult breast cancer with axillary lymph node metastasis: Nationwide retrospective study
Authors: Sohn G , Son BH , Baek S , Lee S , Lee Y , Kim HJ , Ko BS , Yu J , Lee JW , Ahn S-H 
Published: August 2014

Abstract
Objective
Occult breast cancer (OBC) is a rare presentation which accounts for 0.3-1.0% of all breast cancers. In spite of limited information, there is no consensus regarding the prognostic factors and treatment of OBC. This retrospective study intends to evaluate the overall survival and prognostic factors of occult breast cancer (OBC) in Korea.
Method
This study included 142 pathologic occult breast cancer patients from January 1990 to December 2009, identified from Korean Breast Cancer Society cancer registry. All patients had pathologically positive axillary lymph node (N1-N3) along with pathologically & radiologically negative in-breast lesion (T0/Tx) based on retrospective review of database. Among 142 patients, 32 patients had only axillary lymph node dissection (ALND), 56 patients had breast conserving operation (BCO) with ALND and 54 patients had mastectomy with ALND. 96 patients (96%) had N1 disease, 23 patients (16.2%) had N2 disease and 23 patients (16.2%) had N3 disease.
Results
There was no significant statistical difference in overall survival among different operation method, which is ALND only, BCO with ALND, mastectomy with ALND (p = 0.061), considering that 12 patients (37.5%) among 32 patients who only had ALND had N3 disease comparing that only 7 (12.5%) out of 56 patients and 4 (7.4%) out of 54 patients had N3 disease in BCO with ALND and mastectomy with ALND group separately. Univariate analysis revealed that only nodal status was significant prognostic factor (p = 0.0004), and other factors including radiotherapy (p = 0.696), chemotherapy (p = 0.302), estrogen receptor positivity (p = 0.144), progesterone receptor positivity (p = 0.254), total number of removed lymph node (p = 0.586) didn't show statistical difference in overall survival.
Conclusions
This study suggests that OBC patients who only had ALND showed similar outcomes when comparing with patients who had BCO with ALND or mastectomy with ALND. Also only nodal status might be independent predictors for poor outcomes of occult breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-54.
Abstract P6-07-07: Febrile neutropenia primary prophylaxis with granulocyte-colony stimulating factors (G-CSF) in breast cancer
Authors: Younis T , Rayson D , Skedgel C 
Published: August 2014

Abstract
Background: Febrile neutropenia (FN) during adjuvant chemotherapy is associated with significant morbidity, mortality risk and incremental costs. It could also lead to chemotherapy dose reductions and worse cancer outcomes. Patients who develop FN are often prescribed secondary G-CSF prophylaxis with subsequent chemotherapy cycles to decrease the risk of further episodes of infection. Practice guidelines also recommend primary G-CSF prophylaxis for: i) patients treated with chemotherapeutic regimens associated with FN risks &gt; 20% and ii) patients treated with regimens associated with 10-20% FN risk in the presence of other patient-related factors that further increase the risk of FN. The adoption of primary G-CSF prophylaxis in clinical practice however depend on the “value for money” associated with G-CSF prophylaxis at various FN risks, where incremental cost-utility values below $100,000 per quality adjusted life year (QALY) gains are generally considered to be cost-effective. Aim: To examine the “value for money” associated with primary and secondary G-CSF prophylaxis strategies, compared with a no G-CSF strategy, for adjuvant chemotherapy in breast cancer at varying FN risks. Methods: The incremental costs and QALYs associated with G-CSF prophylaxis (primary or secondary) were examined through a decision analysis framework that incorporated i) upfront costs of G-CSF treatment (primary or secondary); ii) varying rates of baseline FN risks and iii) downstream costs and QALY gains associated with adjuvant chemotherapy based on chemotherapy dose levels (0, -1, and -2) and G-CSF prophylaxis. The primary analysis involved adjuvant TC (taxotere & cyclophosphamide) chemotherapy regimen delivered every three weeks for four cycles. Probabilities and utilities were derived from the literature, and treatment costs were based on local resources. The robustness of the model to plausible ranges of uncertainty around key parameters / assumptions was examined in sensitivity analyses. Results: Primary G-CSF prophylaxis was a cost-effective strategy compared with secondary G-CSF prophylaxis in the base case scenario. The “value for money” associated with primary G-CSF prophylaxis however was dependant on the baseline FN risk without G-CSF, and assumptions around the impact of chemotherapy dose reductions on breast cancer relapse and mortality. Two way sensitivity analyses illustrated plausible combinations of baseline FN risks and detrimental impact of reduced chemotherapy dose associated with favorable value for money. Conclusions: Primary G-CSF prophylaxis overall appears to be a cost-effective strategy for patients at high FN risk. The FN threshold at which primary G-CSF is associated with good value for money is however dependent on the potential detrimental impact of reduced chemotherapy dose on breast cancer outcomes.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-07.
Abstract P6-08-02: Quality of life in breast cancer patients after breast conservation surgery or modified radical mastectomy - A comparative study from a tertiary cancer care center in India
Authors: Pudumjee SB , Mane AD , Deshmukh SP , Bokil KP , Choudhary AG , Sane SP 
Published: August 2014

Abstract
Background: The research in QOL of breast cancer patients has been predominantly focussed on the western world and has yielded mixed results. However there is a paucity of QOL data in Indian patients. Due to increasing incidence of breast cancer in the Indian population, it is imperative to look into the QOL experienced by patients after treatment.
Aim: The aim of the study was to assess any difference in QOL experienced by women having undergone Breast Conservation Surgery (BCS) and by those having undergone a Modified Radical Mastectomy (MRM) in a tertiary cancer care center.
Methodology: Total 75 patients were assessed prospectively (MRM = 43, BCS = 32) using the Functional Assessment of Cancer Therapy - Breast (FACT - B) Version 4 scale. Patients diagnosed with Stage I, II or III breast cancers were assessed after 6 months post completion of all treatment.
Results: The Mann Whitney - U test showed that the overall QOL did not differ significantly across the two groups but the FACT - G (General) and Functional Well Being (FWB) subscale showed that BCS patients fared better than those of MRM with P-values of 0.033 and 0.031 respectively(Table 1). MRM patients did not experience significantly lower body image and decreased sexual functioning when compared to the BCS patients.
Conclusions: There was no significant difference between the QOL experienced by patients of MRM and BCS. However BCS patients did report higher levels of functionality as well as general QOL without considering factors specific to breast cancer. The lack of difference between body image and sexual functioning was in sharp contrast to the findings in western literature and can be explained by the cultural variance.
Implications: This study will serve the purpose of establishing the need for further culturally appropriate investigations into QOL of breast cancer patients as well as lend impetus to more targeted, culture appropriate forms of psychosocial intervention.
Difference between QOL for BCS and MRM patients BCS (Median)MRM (median)P-valuePhysical Well Being25.5240.088Social Well Being25.435240.266Emotional Well Being23200.188Functional Well Being27.5250.031*Breast Cancer Subscale26.5270.855Trial Outcome Index78730.133FACT - G99.5910.033*FACT - B124.51170.065*significant at the 0.05 level
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-02.