bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-05-05: Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal breast cancer patients
Authors: Doostan Iman , Moulder Stacy L , Hunt Kelly K , Keyomarsi Khandan 
Published: May 2015

Abstract
Almost seventy percent of all breast cancer patients have estrogen receptor (ER) positive tumors requiring hormonal therapy. Aromatase inhibitors (AIs) are considered as the first line hormonal therapy for ER+ post-menopausal patients. However, resistance to these drugs remains a major challenge in clinic and the biology of such resistance is not clear.
Previous studies have shown that cyclin E pathway, a key regulator in the G1 to S transition of cell cycle, is deregulated in breast cancer. Full-length cyclin E is abnormally cleaved into low molecular weight isoforms (LMW-E) that renders patients to poor survival. Here we hypothesize that cyclin E deregulation can confer resistance to AIs. To address this, we engineered aromatase overexpressing MCF7 cells to overexpress LMW-E under doxycycline inducible promoter. Full-length cyclin E, GFP and empty vector transfected cells were also generated and used as controls. Our results indicated that AIs inhibited proliferation by arresting the cells at G1 phase of the cell cycle. However, LMW-E expression significantly enhanced proliferation of the cells when treated with AIs. In addition, LMW-E bypassed G1 arrest following AI treatment. At the molecular level, AIs decreased CDK2, pCDK2, and Rb levels and attenuated Rb phosphorylation. However, these effects were completely rescued only when LMW-E was expressed. Moreover, using an in vitro kinase assay we indicated that AIs decreased CDK2 kinase activity while LMW-E expression reversed this effect by increasing CDK2 enzymatic activity. Taken together, these results suggest that LMW-E inactivates Rb protein as a tumor suppressor and renders the cells to bypass G1 checkpoint following AI treatment. In addition, this study provides early evidence that CDK2 inhibitors could be beneficial in combination with AIs for LMW-E expressing tumors. Currently we are investigating whether LMW-E can bypass the activity of AIs using inducible breast cancer cell line xenograft. We are also examining the correlation between cyclin E status and response to treatment in a cohort of patients who received AIs in the neo-adjuvant setting.
Citation Format: Iman Doostan, Stacy L Moulder, Kelly K Hunt, Khandan Keyomarsi. Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-05-05.
Abstract P5-06-04: The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score
Authors: Wang Yan , Cairo Stefano , Deas Olivier , Hartman Anne-Renee , Jones Joshua , Gutin Alexander , Lanchbury Jerry , Sangale Zaina , Solimeno Cara , Judde Jean-Gabriel , Timms Kirsten , Wilcoxen Keith 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with that of BRCA1/2 mutation driven breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by dysfunction of genes other than BRCA1 or BRCA2.
Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. Previously, we demonstrated that a subset of basal breast cancer (BBC) patient-derived xenograft (PDX) models responded robustly to single agent niraparib treatment. To understand the selectivity observed, the samples from a collection of 37 BBC PDX models have been subjected to homologous recombination deficiency (HRD) analysis. HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using three algorithms (LOH, TAI and LST scores), and the final HRD score is the sum of the LOH+TAI+LAST scores.
Niraparib’s antitumor activity was investigated in patient derived BBC models with various HRD scores. The correlation between niraparib efficacy, HRD score and BRCA deficiency will be discussed.
Citation Format: Yan Wang, Stefano Cairo, Olivier Deas, Anne-Renee Hartman, Joshua Jones, Alexander Gutin, Jerry Lanchbury, Zaina Sangale, Cara Solimeno, Jean-Gabriel Judde, Kirsten Timms, Keith Wilcoxen. The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-04.
Abstract P5-07-06: Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer
Authors: King Jamie L , Saavedra Harold I 
Published: May 2015

Abstract
The centrosome is the cellular organelle responsible for accurate chromosome segregation. In normal cellular function, regulation of the centrosome duplication cycle in concert with the cell cycle is necessary for accurate passage of genetic information. However, when modulators of the cell and/or centrosome duplication cycles are deregulated, this process can result in centrosome amplification (CA, the acquisition of more than two centrosomes), leading to improper segregation of chromosomes and genomic instability. CA generates low-level aneuploidy (which is tolerated) and polyploidy (selected against when checkpoints are present). An integral goal in the field of centrosome biology is to characterize how alterations in modulators of CA influence disease development. In cancer, CA is associated with aggressive tumor types and metastasis and is likely to affect response to treatment. However, the full role of CA in tumorigenesis is poorly understood. Specifically in breast cancer, CA is observed in pre-cancerous lesions, which suggests CA in conjunction with genomic instability is an early contributor to tumorigenesis. In an effort to study mechanisms associated with CA, we are investigating the function of CA in in vitro and in vivo breast cancer models. Our lab and others have detected that TTK (MPS1) kinase, a proposed modulator of centrosome duplication, is overexpressed in Her2+ breast cancer cell lines at the mRNA and protein level compared to non-transformed mammary epithelial cells. We hypothesize that overexpression of TTK leads to CA and that inhibiting TTK expression in cancer cells will prevent active generation of CA and CIN (chromosome instability), leading to suppressed tumorigenic properties and further cancer evolution. Preliminary data shows that transient knockdown of TTK via siRNA attenuates the degree of CA in Her2+ breast cancer cells. Additional preliminary data shows that stable abrogation of TTK via shRNA can inhibit the proliferation of Her2+ breast cancer cells but does not alter expression of some members in the intrinsic apoptotic pathway. Ongoing studies will address the impact of altering TTK expression on CA, CIN, downstream centrosomal duplication signaling and tumorigenic properties of breast cancer cells. The results of these studies will address the mechanistic complexities, such as what centrosomal signaling pathways associated with TTK are underlying CA in breast cancer. We believe this work will help discern how deregulated centrosome regulatory molecules influence mammary tumorigenesis and/or responses to treatment.
Citation Format: Jamie L King, Harold I Saavedra. Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-06.
Abstract P5-17-05: It's as simple as ABC: Can we improve the provision of coordinated medical and supportive care to patients with advanced breast cancer?
Authors: Greenberg Sally , Pitcher Meron , Mann Bruce , Hendry Kathleen , Shanahan Kerry , Fisher Melanie K , Foo Jung H 
Published: May 2015

Abstract
Back ground: International and local guidelines regarding advanced breast cancer (ABC) management recommend coordinated care, discussion in multi-disciplinary meetings (MDM), breast care nurse (BCN) involvement and supportive care screening (SCS). There was concern among clinicians, at three University affiliated hospitals in Melbourne Australian, that these were not routinely performed for all patients at our hospitals. A WCMICS service improvement grant was used to design a Model of Care (MOC) aiming to address these deficiencies.
Method: A 6 month retrospective audit of all new ABC patients was conducted at each institution. We reviewed timing and details of diagnosis, MDM discussions, BCN involvement, SCS and communication with primary care physicians (PCP). Surveys/ interviews of PCP, patients and oncology clinicians were conducted. A best practice MOC was developed, piloted for three months and evaluated.
Results: The new MOC resulted in an increased proportion of patients discussed in MDM (from 33% to 88%), reviewed by a BCN (from 30% to 80%), and improved provision (from 61% to 90%) and timing (median 20 down to 16 days) of communication with PCP. 50% of patients interviewed in both the baseline and subsequent evaluation surveys did not feel their care was well coordinated between specialists and PCP.
Conclusions: A best practice MOC for patients with newly diagnosed ABC is possible to implement across a number of institutions with improvements in the provision of coordinated medical and supportive care. Further improvements can be made in coordination of care between PCP and specialists.
Citation Format: Sally Greenberg, Meron Pitcher, Bruce Mann, Kathleen Hendry, Kerry Shanahan, Melanie K Fisher, Jung H Foo. It's as simple as ABC: Can we improve the provision of coordinated medical and supportive care to patients with advanced breast cancer? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-17-05.
Abstract P5-18-02: Trastuzumab interruption for treatment-induced cardiotoxicity in HER2 positive early breast cancer
Authors: Yu Anthony F , Yadav Nandini U , Lung Betty Y , Eaton Anne A , Thaler Howard T , Hudis Clifford A , Dang Chau T , Steingart Richard M 
Published: May 2015

Abstract
Background
Trastuzumab (H) improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC), especially when administered after an anthracycline (A). H interruption is recommended for significant asymptomatic or symptomatic declines in left ventricular ejection fraction (LVEF). It is unclear how frequently TIC leads to H interruption, and the subsequent management is variable in clinical practice.
Methods
Patients (pts) with HER2-postive early breast cancer receiving adjuvant H with chemotherapy between January 2005 and October 2010 were studied (n=608). Tumor characteristics, chemotherapy regimen, cardiac risk factors, LVEF (at baseline and during treatment), and treatment interruption were obtained from the medical record. We evaluated the incidence, time of occurrence, management, and associated risk factors of H interruption due to TIC.
Results
Median age was 51 years (range 26-81); 488 (80%) pts had A prior to H administration. H was interrupted in 108 (18%) pts. Cumulative dose of H was lower among pts in the interrupted group (median 86 vs. 108 mg/kg, p &lt; 0.0001). The most common reason for interruption was TIC (66 of 108 pts): 20 (30%) had symptomatic congestive heart failure and 46 (70%) had asymptomatic decline in LVEF. Of the 66 pts, 55 (83%) were referred to a cardiologist and 36 (55%) were prescribed a new cardiac medication. The mean LVEF at baseline, at time of cardiotoxicity diagnosis, and at follow-up after interruption of H was 63%, 45%, and 55%, respectively. Pts with H interruption for TIC were older (54 vs. 50 years, p=0.014) with lower LVEF before A (63 vs. 67%, p&lt;0.0001) and before H therapy (62% vs. 67%, p&lt;0.0001), compared to those with continuous H treatment. Thirty-three of 66 pts were re-treated with H, and 5 pts had a significant recurrent decline in LVEF.
Conclusion
At our institution, interruption of H therapy is common and most often due to TIC, from both A and H, with the majority of pts receiving A prior to H. Risk factors associated with H interruption were older age and lower LVEF prior to A and H administration. Cardiac dysfunction improved after interruption of treatment but did not fully recover to baseline. Strategies to prevent cardiotoxicity and minimize H treatment interruption should be investigated to prevent persistent LV dysfunction in affected pts.
Citation Format: Anthony F Yu, Nandini U Yadav, Betty Y Lung, Anne A Eaton, Howard T Thaler, Clifford A Hudis, Chau T Dang, Richard M Steingart. Trastuzumab interruption for treatment-induced cardiotoxicity in HER2 positive early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-02.
Abstract P6-01-03: Change of HER2 status following neoadjuvant systemic therapy in primary breast cancer patients
Authors: Yoshida Atsushi , Hayashi Naoki , Yagata Hiroshi , Suzuki Koyu , Nakamura Seigo , Yamauchi Hideko 
Published: May 2015

Abstract
Background: The incidence of change in HER2 status in primary breast cancer after neoadjuvant chemotherapy (NAC) and whether the prognosis is affected by the change in HER2 status is not well known.
Patients and Methods: Five hundred and eighty-eight patients who were treated with anthracycline- and/or taxane-based NAC and had non-pathologic complete response between 2001 and 2008 in our hospital were enrolled. Human epidermal growth factor receptor-2 (HER2) status was assessed in specimen by needle biopsy before NAC and on the residual tumor of surgical specimen. We determine the impact of change in HER2 status on recurrence-free survival (RFS). Twenty-eight patients had received trastuzumab with NAC, and 57 patients had received trastuzumab as adjuvant therapy. HER2-positive was defined as 3+ by immunohistochemistry and/or amplification by fluorescent in situ hybridization. Association between change in HER2 status after NAC and clinicopathologic factors, including age, clinical T stage, estrogen receptor (ER), progesterone receptor (PR), Nuclear grade (NG), lymphovascular invasion (LVI) and Trastuzumab usage (NAC and Adjuvant setting) were determined.
Result: A median follow-up period was 57 months (range, 3 to 131 months). Four hundred eighty-nine of the 588 patients (83.1%) had HER2-negative tumors and 99 patients (16.8%) had HER2-positive tumor before NAC. In 11 of the 489 patients (2.2%) HER2-negative changed to HER2-positive.In 33 of the 99 patients (30%) HER2-positive changed to HER2-negative. In clinicopathologic factors, ER and PR positive before NAC were associated with incidence of change in HER2 status after NAC. Receiving trastuzumab was not correlated with incidence of change in HER2 status. In terms of RFS, there was no difference between patients with and without change in HER2 status in both of the 489 patients with HER2-negative tumors and 99 patients with HER2-positive tumors before NAC (p=0.26, p=0.23, respectively).
Conclusion: We herein reported the incidence of change in HER2 status after NAC with the largest sample size. However, change in HER2 status did not seems to affect prognosis. Further prospective study is needed to confirm the prognostic impact of change in HER2 status.
Citation Format: Atsushi Yoshida, Naoki Hayashi, Hiroshi Yagata, Koyu Suzuki, Seigo Nakamura, Hideko Yamauchi. Change of HER2 status following neoadjuvant systemic therapy in primary breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-03.
Abstract P6-01-15: Expression of high affinity folate receptor in breast cancer brain metastasis
Authors: Leone Jose P , Bhargava Rohit , Lee Adrian , Brufsky Adam 
Published: May 2015

Abstract
Background: Folic acid is required by proliferating cells for the synthesis of nucleotide bases among other tasks. The high affinity folate receptor (HFR) is a membrane protein that is upregulated in several cancers of epithelial origin and rarely present in most normal cells. High expression of HFR has been documented in ovarian, breast, kidney, uterine and lung cancers. In breast cancer patients, HFR is overexpressed in 33% of primary tumors (PT) and this is associated with poor prognosis. The HFR expression in breast cancer brain metastases (BCBM) is unknown. The aim of this study was to analyze the incidence of HFR expression in BCBM and its role in the prognosis of this high-risk patient subgroup.
Methods: We analyzed a database of 42 patients who underwent craniotomy with resection of breast cancer brain metastasis (BCBM). Of those, we collected 19 brain metastasis (BM) and 13 PT. HFR status was assessed by immunohistochemistry. Log-Rank test analyzed differences in overall survival (OS) between groups.
Results: Median age was 51 years (range 24-74). Median follow-up was 4.2 years (range 0.6-18.5). HFR was positive in 4/19 BM (21.1%) and in 1/13 PT (7.7%). Positive samples had low H-scores (range 1-50). Staining with H&E revealed that 11/19 BM (57.9%) and 7/13 PT (53.8%) had apocrine differentiation. Analysis of OS showed no difference between patients with positive HFR (median OS 48 months) and negative HFR (median OS 69 months) (P=0.25). Similarly, there was no difference in OS between patients with apocrine differentiation (median OS 63 months) and those without apocrine differentiation (median OS 69 months) (P=0.49).
Conclusions: To the best of our knowledge, this is the first analysis of HFR expression in BCBM. While previous studies associated the presence of HFR with worse prognosis; in this cohort of high-risk patients, HFR was positive in only 21.1% of BM with low levels of positivity. Around half of our patients had apocrine differentiation. Neither the status of HFR nor the presence of apocrine features had impact in OS in our cohort.
Citation Format: Jose P Leone, Rohit Bhargava, Adrian Lee, Adam Brufsky. Expression of high affinity folate receptor in breast cancer brain metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-15.
Abstract P6-12-04: Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy
Authors: Wang Lili , Yang Zhengduo , Xia Qing , Chen Haijun , Cai Guoshuai , Wild Christopher , Zhou Jia , Shen Qiang 
Published: May 2015

Abstract
Radiation therapy plays an important role in controlling the growth and progression of breast cancer. However, its efficacy is limited by the radiation-associated toxicity to normal tissue, and the intrinsic or acquired radioresistance developed in cancer cells. It was well documented that radiation onto cancer tissues cause complex changes in gene expression patterns. Thus, it may be possible to manipulate the expression of specific genes in cancer cells to increase radiosensitivity and reduce radioresistance. Accumulating studies strongly demonstrated that signal transducers and activators of transcription 3 (STAT3) is involved in cell survival, proliferation, inflammation, invasion, metastasis, angiogenesis and immune responses. Particularly, STAT3 is activated by ionizing radiation. We hypothesized that blocking STAT3 will increase sensitivity to irradiation in cancer cells. To this end, we synthesized a series of novel STAT3 inhibitors to address the challenge of radioresistance in breast cancer cells including metastatic and triple-negative lines. Among them, the compound HJC0152 and HJC0123 displayed significant inhibition of proliferation of MDA-MB-231, MCF-7 and MCF-7/Adr in dose and time dependent manners. HJC0152 and HJC0123 also induced apoptosis and necrosis in comparison to the control cells. We also found that these STAT3 inhibitors induce apoptosis of MDA-MB-231, MCF-7 and MCF-7/Adr cells by inhibiting anti-apoptotic protein Bcl-2 expression, increasing the expression of apoptotic effector protein caspase-3 and Bax. In addition, we found that HJC0152 and HJC0123 in combination with X-ray irradiation induce G2/M cell cycle arrest in MDA-MB-231, MCF-7 andMCF-7/Adr cells. The new STAT3 inhibitors increased the radiosensitivity of MDA-MB-231, MCF-7 and MCF-7/Adr cell lines, inhibited radiation-induced DNA damage repair, and promoted cells to enter mitosis, a phase more sensitive to irradiation. These changes were accompanied with decreased activation of STAT3 and decreased expression of the STAT3 downstream gene, Bcl-2. Our findings suggest that STAT3 blockade may represent an effective strategy to overcome radiation resistance, using STAT3 inhibitors as radiation sensitizers to restore the sensitivity of cancer cells to radiation therapy.
Citation Format: Lili Wang, Zhengduo Yang, Qing Xia, Haijun Chen, Guoshuai Cai, Christopher Wild, Jia Zhou, Qiang Shen. Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-04.