bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-12-04: De-escalating doses of letrozole in post menopausal women at high risk for breast cancer
Authors: Lopez Ana Maria , Chow Hsiao Hui Sherry , Frank Denise , Puthi Sandhya , Boughey Judy , Hsu Paul , Guillen Jose , Perloff Marjorie , Ley Michelle , Lang Julie E
Published: May 2015

Background: Although breast cancer (BC) may occur at any age, its prevalence is greater postmenopause. Greater than 75 % of postmenopausal BCs are hormone dependent. Aromatase inhibitors suppress postmenopausal estrogen biosynthesis. Letrozole has demonstrated efficacy against BC in the adjuvant and metastatic setting at the treatment dose of 2.5 mg daily. Its potential role in BC prevention has been inferred from reductions in contralateral BCs. Its side effect profile, similar to other AIs, includes exacerbation of menopausal symptoms that negatively impact quality of life (QOL) and may result in discontinuation of the drug. Both anastrazole and exemestane have been demonstrated to reduce BC in high-risk women.

Hypothesis: Lower and intermittent doses of letrozole effectively suppress estrogen in the high-risk postmenopausal woman and provide a better side effect profile.

Methods: A randomized, double-blind study comparing the impact of varying letrozole doses (2.5 mg daily, 2.5 mg MWF, 1.0 mg MWF, or 0.25 mg MWF) on estrogen suppression and side effects--lipids, bone resorption, menopause, and QOL-- was conducted. Participants randomized to intermittent dosing received placebo on nontreatment days.

Results: 112 participants were enrolled at 2 clinical sites. Mean patient age was 62.8 years, and average BMI was 29.8. Analysis of available data after 24 weeks of therapy revealed statistically significant increase in triglycerides (N=94): 114.67±48.39 to 125.79±54.31 (p<0.01); vasomotor symptoms (N=95): 2.25±1.26 to 2.74±1.67 (p<0.01); and C-telopeptide (N=75): 0.39±0.23 to 0.55±0.28 (p<0.0001). Statistically significant decrease in estradiol (N=68): 5.57±5.19 to 1.26±1.41 (p<0.0001) and estrone (N=68): 22.39±13.02 to 1.64±2.66 (p<0.0001) were observed. No differences in QOL (SF 36) were noted after letrozole treatment. P-values were derived from paired t-test (signed rank test) for the difference between baseline and after 24 weeks of study drug.

Conclusions: De-escalating doses of letrozole suppress postmenopausal estrogen effectively and result in statistically significant increases in triglycerides, C-telopeptide and vasomotor symptoms without impact on QOL. Presentation will include unblinded intervention arm outcomes.

Citation Format: Ana Maria Lopez, Hsiao Hui Sherry Chow, Denise Frank, Sandhya Puthi, Judy Boughey, Paul Hsu, Jose Guillen, Marjorie Perloff, Michelle Ley, Julie E Lang. De-escalating doses of letrozole in post menopausal women at high risk for 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 P5-12-04.
Abstract P5-15-22: Evaluation of quality of life in patients with advanced and metastatic breast cancer proposed for palliative chemotherapy and best supportive care versus best supportive care
Authors: Ciuhu Anda-Natalia T , Rahnea Nita Gabriela I , Popescu Mihaela T , Rahnea Nita Roxana Andreea D
Published: May 2015

Background:

In Romania many patients neglect their symptoms and present to the doctor in advanced stages of cancer. In the case of patients with breast cancer who present with very advanced locoregional disease (ulcerated or hemorrhagic tumors) and symptomatic metastatic disease (visceral or skeletal pain, dyspnea), the choice between chemotherapy/hormonal therapy and best supportive care and only best supportive care became very difficult.

Objective:

Evaluation of quality of life in patients with advanced and metastatic breast cancer proposed for palliative chemotherapy and best supportive care versus best supportive care

Materials and methods:

In the last 6 month of the year 2013, 57 patients with advanced and metastatic breast cancer were randomized to either chemotherapy/hormonal therapy in addiction to best supportive care or to best supportive care. The patients were naive to chemotherapy, with performance status – ECOG between 2 and 3 and had symptomatic disease. The randomization of patients was made according to their choice. The performance status and the symptoms were evaluated at the baseline and, later, at each admission in the Oncology Palliative Care Department.

Results:

More patients in the chemotherapy group (92.68%, 38/41) had an improve quality of life compared to those in the best supportive care group (56.25 %, 9/16). The overall survival was longer in the chemotherapy group.

Conclusions:

The results show that chemotherapy/hormonal therapy improve the quality of life and overall survival in very advanced locoregional disease and symptomatic metastatic breast cancer. The number of patients who benefit from chemotherapy and best supportive care is higher versus patients who benefit only from best supportive care.

Key words: chemotherapy/hormonal therapy, best supportive care, breast cancer.

Citation Format: Anda-Natalia T Ciuhu, Gabriela I Rahnea Nita, Mihaela T Popescu, Roxana Andreea D Rahnea Nita. Evaluation of quality of life in patients with advanced and metastatic breast cancer proposed for palliative chemotherapy and best supportive care versus best supportive care [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 P5-15-22.
Abstract P5-16-01: End-of-life outcomes and hospice and palliative care utilization in hospitalized patients with metastatic breast cancer
Authors: Parkes Amanda , Shin Jennifer A , Knight Helen , El-Jawahri Areej , Traeger Lara , Temel Jennifer S
Published: May 2015

Background:

Hospitalizations in patients with metastatic cancer occur commonly at the end of life but have not been well-described in those with metastatic breast cancer (MBC). The goal of this study was to describe the reasons for admission, end-of-life outcomes, and hospice and palliative care utilization in hospitalized patients with MBC.

Methods:

We identified all patients with MBC who had their first hospital admission (index admission) at Massachusetts General Hospital since their diagnosis of metastatic disease between 1/1/2009 and 12/31/2010 through a centralized clinical data registry. We collected demographic and clinical information and data on all hospital admissions and utilization of palliative care and hospice services during a three-year follow-up period.

Results:

We identified 123 patients hospitalized for the first time since their diagnosis of MBC. The median number of hospital admissions during the three-year follow-up period was 2 (range 1 to 17). Uncontrolled symptoms accounted for half (62/123, 50%) of the index admissions [20 (16%) with central nervous system systems, 17 (14%) with respiratory symptoms, 10 (8%) with pain, 9 (7%) with gastrointestinal symptoms, 4 (3%) with failure to thrive, and 2 (2%) with dehydration]. The majority of patients (93/123, 76%) died during the follow-up period. The median time from first hospitalization to death was 6 months (range 0 to 53). Among patients who died, 20/93 (22%) died in the hospital and 49/93 (53%) died within 14 days of hospital discharge. Among the deceased group, the inpatient palliative care team evaluated 53/93 (57%) of patients at least once during an admission, but only 18/93 (19%) patients attended an outpatient palliative care clinic appointment. A minority of patients who died (27/93, 29%) were referred to hospice upon discharge. An additional 34/93 (37%) patients who died were referred to hospice from the outpatient setting.

Conclusions:

Hospitalized patients with MBC are commonly admitted for uncontrolled symptoms. They have a poor prognosis, and approximately half die within two weeks of a hospital admission. However, only a minority receive outpatient palliative care or are referred to hospice services from the inpatient setting. These findings highlight the need to develop interventions to improve end-of-life care for patients with MBC who are hospitalized.

Citation Format: Amanda Parkes, Jennifer A Shin, Helen Knight, Areej El-Jawahri, Lara Traeger, Jennifer S Temel. End-of-life outcomes and hospice and palliative care utilization in hospitalized patients with metastatic 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 P5-16-01.
Abstract P6-01-17: AQP3 expression predicts survival in patients with HER2-positive early breast cancer
Authors: Chae Yee Soo , Lee Soo Jung , Lee Jeeyeon , Jung Jin Hyang , Park Ho Yong
Published: May 2015

Background: Recent studies have revealed aquaporins (AQPs) as targets for novel anti-tumor therapy, since they likely play a role in carcinogenesis, tumor progression, and invasion. Accordingly, we analyzed the prognostic impact of AQP3 expression and polymorphisms in a number of patients with early breast cancer (EBC).

Patients and Methods: AQP3 expression was investigated on the basis of the immunohistochemistry of tissue microarray specimens from 447 EBC patients who underwent surgery between 2003 and 2008. We scored the staining intensity (0 through3) and percentage of positive tumor cells (0 through 4), and the staining score was defined as sum of these scores used to categorize the AQP3 expression as negative (0 through 2), weak (3 through 5), or strong (6 or more). For AQP3 polymorphisms, seven SNPs (rs10813981, rs34391490, rs591810, rs2227285, rs2228332, rs17553719, and rs3860987) were selected using in silico analysis and genotyped using the Sequenom MassARRAY.

Results: A total of 180 (40.3%) of the patients were identified as AQP5-positive (staining score >2), including 86 (19.2%) cases of strong expression (stating score >5). In a univariate analysis, AQP3 expression was significantly associated with survival for the patients with HER2-overexpressing EBC. Moreover, a multivariate survival analysis revealed that AQP3 expression was an independent prognostic marker of disease-free survival (DFS: HR=3.137, 95%CI=1.079-9.125, p=0.036; Distant DFS: HR=2.784, 95%CI=0.921-8.414, p=0.070) for the HER2-overexpressing EBC patients. Meanwhile, none of selected AQP3 polymorphisms were related with AQP3 expression in tumor tissue nor survival in the current study.

Conclusion: AQP3 expression in tumor tissue may be considered as a potential prognostic marker in patients with HER2-overexpressing EBC after curative surgery.

Citation Format: Yee Soo Chae, Soo Jung Lee, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park. AQP3 expression predicts survival in patients with 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 P6-01-17.
Abstract P6-03-04: TGF-β receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer
Authors: Jovanovic Bojana , Beeler J Scott , Pickup Michael W , Chytil Anna , Gorska Agnieszka E , Ashby William J , Lehmann Brian D , Zijlstra Andries , Pietenpol Jennifer A , Moses Harold L
Published: May 2015

Introduction: There is a major need to better understand the molecular basis of triple negative breast cancer (TNBC) in order to develop effective therapeutic strategies. Using gene expression data from 587 TNBC patients we previously identified six subtypes of the disease, among which a Mesenchymal-Stem Like (MSL) subtype. The MSL subtype has significantly higher expression of the transforming growth factor beta (TGF-β) pathway-associated genes relative to other subtypes, including the TGF-β receptor type III (TβRIII). We hypothesize that TβRIII is tumor promoter in mesenchymal-stem like TNBC cells.

Methods: Representative MSL cell lines SUM159, MDA-MB-231 and MDA-MB-157 were used to study the roles of TβRIII in the MSL subtype. We stably expressed short hairpin RNAs specific to TβRIII (TβRIII-KD). These cells were then used for xenograft tumor studies in vivo; and migration, invasion, proliferation and three dimensional culture studies in vitro. Furthermore, we utilized human gene expression datasets to examine TβRIII expression patterns across all TNBC subtypes.

Results: TβRIII was the most differentially expressed TGF-β signaling gene in the MSL subtype. Silencing TβRIII expression in MSL cell lines significantly decreased cell motility and invasion. In addition, when TβRIII-KD cells were grown in a three dimensional (3D) culture system or nude mice, there was a loss of invasive protrusions and a significant decrease in xenograft tumor growth, respectively. In pursuit of the mechanistic underpinnings for the observed TβRIII-dependent phenotypes, we discovered that integrin-α2 was expressed at higher level in MSL cells after TβRIII-KD. Stable knockdown of integrin-α2 in TβRIII-KD MSL cells rescued the ability of the MSL cells to migrate and invade at the same level as MSL control cells.

Conclusions: We have found that TβRIII is required for migration and invasion in vitro and xenograft growth in vivo. We also show that TβRIII-KD elevates expression of integrin-α2, which is required for the reduced migration and invasion, as determined by siRNA knockdown studies of both TβRIII and integrin-α2. Overall, our results indicate a potential mechanism in which TβRIII modulates integrin-α2 expression to effect MSL cell migration, invasion, and tumorigenicity.

Citation Format: Bojana Jovanovic, J Scott Beeler, Michael W Pickup, Anna Chytil, Agnieszka E Gorska, William J Ashby, Brian D Lehmann, Andries Zijlstra, Jennifer A Pietenpol, Harold L Moses. TGF-β receptor type III is a tumor promoter in mesenchymal-stem like triple negative 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 P6-03-04.
Abstract P6-06-01: Studies on tumor heterogeneity using a preclinical model of breast cancer caused by genetic alteration of the ATX-LPA axis
Authors: Federico Lorenzo , Jeong Kang Jin , Zhang Dong , Ju Zhenlin , Chong Zechen , Dennison Jennifer B , Mills Gordon B
Published: May 2015

Targeted alterations of the ATX/LPA signaling axis in mice creates a tumorigenic environment from which mammary neoplasias can develop. Using mammary tumors derived from this model, we have established a transplantation procedure in which fragments of different tumors are orthotopically transplanted in syngeneic mice. Under these conditions, primary murine tumors displayed a wide spectrum of growth rates suggesting that alteration of ATX/LPA signaling axis engenders a variety of different breast cancer subtypes with distinctive propensity to progress, which is similarly observed in human neoplastic disease. Comprehensive analysis of high-throughput RNAseq and Reverse Phase Protein Array (RPPA) data revealed that despite being passaged multiple times, tumors retained their distinct growth profiles and also maintained surprisingly stable molecular characteristics. The remarkable consistency in terms of growth, transcriptional landscape, and protein expression demonstrates that in this model a small fragment randomly taken from any region of the tumor can accurately and reproducibly regenerate an entire developmental program when grown in vivo. It follows that each consistent molecular change detected in the tumor likely represents either a marker of the tumor or its mechanistic oncodriver. Using unbiased multidimensional scaling analysis of RNAseq data we have identified tumors that were strictly related to normal mammary tissue in terms of gene expression as well as individual gene signatures that differentiate slow- vs fast-growing tumors. Furthermore, we have identified several stable alterations at a protein level that are commonly found in human breast cancers including cMYC, BRCA2, PARP1, Claudin-7, Her3, and E-Cadherin. These results demonstrate that an orthotopic transplantation procedure in immunocompetent hosts represents a relevant preclinical platform to probe human breast cancer heterogeneity and pinpoint molecular alterations that are mechanistically responsible for malignant behavior.

Citation Format: Lorenzo Federico, Kang Jin Jeong, Dong Zhang, Zhenlin Ju, Zechen Chong, Jennifer B Dennison, Gordon B Mills. Studies on tumor heterogeneity using a preclinical model of breast cancer caused by genetic alteration of the ATX-LPA axis [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 P6-06-01.
Abstract P6-06-02: Molecular characterization of a patient-derived xenograft (PDX) resource for triple negative breast cancer
Authors: Graber Joel H , Keck James G , Airhart Susan D , Bult Carol J , Liu Edison T
Published: May 2015

The Jackson Laboratory (JAX) has developed a resource of human tumors implanted into immune deficient mice (patient derived xenografts; PDX) as a platform for testing standard of care and novel therapeutic options for Triple Negative Breast Cancer. PDX models provide an advantage over cell culture based models for testing therapeutic interventions because they retain properties such as tumor cell heterogeneity that are critical to the biological properties of a patient’s tumor and response to treatment.

Tumor material acquired from biopsy or surgical resection was implanted subcutaneously into the flank of immune deficient NOD-scid IL2r gamma-chain null (NSG) mice. The PDX resource currently contains 21 established breast cancer PDX models (12 TNBC) with 24 additional models currently in development. Two of the established TNBC PDX models have BRCA1 mutations. The median age of the patients from whom tumor material was obtained for all breast models is 53 (45-89).

Tumors that successfully engrafted were characterized for somatic mutations using the new JAX Clinical Cancer Panel, Copy Number Variants using the Affymetrix human 6.0 SNP array, and gene expression using both Affymetrix U133 plus v2 and RNA-Seq. Normalized gene expression was analyzed for characteristic patterns in a pan-cancer approach across all PDX models and further compared with the previously identified TNBC molecular subtypes (Lehmann et al. 2011. JCI 121:2750-2767). The combination of principal components analysis and classification via expression pattern resulted in putative matches of models to most of the known molecularly defined subtypes of TNBC tumors.

Tumor bearing mice for the TNBC PDX models have been treated with docetaxel, cisplatin, cyclophosphamide and doxorubicin. Preliminary studies of tumor response to these treatment regimes revealed systematic differences that can be correlated with features of the genomic analysis, including expression subtype characterization.

The JAX collection of TNBC cancer PDX models is a well-annotated, publically available resource of models with deep genomic characterization and standard of care therapy response data for use in the development of advanced therapeutic options. Genomically defined subgroups within the collection suggest strategies to refine patient selection and treatment algorithms. Information about the models along with summarized genomic data is publicly available at the Mouse Tumor Biology database PDX web portal (http://tumor.informatics.jax.org).

Citation Format: Joel H Graber, James G Keck, Susan D Airhart, Carol J Bult, Edison T Liu. Molecular characterization of a patient-derived xenograft (PDX) resource for triple negative 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 P6-06-02.
Abstract P6-06-04: The role of sphingosine kinase 1 in breast carcinogenesis
Authors: Shimizu Yoshiko , Furuya Hideki , Tamashiro Paulette M , Iino Kayoko , Rosser Charles J , Kawamori Toshihiko
Published: May 2015

Introduction: The bioactive sphingolipids, ceramide/sphingosine and sphingosine 1-phosphate (S1P) possess opposite effects on cell fate. Sphingosine kinase 1 (SphK1) is an enzyme that principally regulates the balance or the "rheostat" of the sphingolipids by phosphorylating sphingosine to form S1P. In this study, we investigated the effect of SphK1 deficiency on HER2/neu-induced mammary carcinogenesis using a MMTV-neu transgenic (Tg) mice model. Methods: MMTV-neu Tg mice were crossbred with SphK1 knockout (KO) mice to generate MMTV-neu Tg mice with KO or wild-type for SphK1 gene. The number and size of the palpable tumors were recorded weekly until mice reached 35 weeks of age or the largest tumor diameter reached 20 mm in size. At necropsy, tumors and blood were collected for analysis. The sphingolipid profiles in blood were analyzed using tandem mass spectrometry. Results: The incidences of mammary tumor development in the homozygous SphK1 KO (1/13; 8%) and heterozygous SphK1 KO (11/44; 26%) were significantly reduced (P=0.0112 and 0.0208, respectively) when compared to wild-type mice (8/13; 62%). The mammary tumor multiplicity was significantly reduced in homozygous SphK1 KO (0.08±0.08; P=0.0036) when compared to wild-type mice (0.69±0.17). The S1P levels in blood were significantly decreased in homozygous SphK1 KO mice (P<0.0001), while sphingosine levels were significantly increased in the blood of heterozygous SphK1 KO mice (P<0.001). In both homozygous and heterozygous SphK1 KO mice, the blood level of C16:0-Ceramide was significantly increased (P<0.001). Conclusion: The results provide novel evidence that SphK1 mediates HER2/neu-induced mammary carcinogenesis by regulating the ceramide/sphingosine-S1P "rheostat". Thus, we propose that SphK1 inhibition may be a novel therapeutic option in the treatment of HER2 breast tumors.

Citation Format: Yoshiko Shimizu, Hideki Furuya, Paulette M Tamashiro, Kayoko Iino, Charles J Rosser, Toshihiko Kawamori. The role of sphingosine kinase 1 in breast carcinogenesis [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 P6-06-04.
Abstract P6-08-39: Influence of lifestyle factors and tumor cell dissemination in 632 early breast cancer patients
Authors: Aktas Bahriye , Frackenpohl Anna , Hauch Siegfried , Kraus Johann , Kestler Hans Armin , Kimmig Rainer Klaus , Kasimir-Bauer Sabine
Published: May 2015

Introduction: Influence of lifestyle behaviour in risk of developing breast cancer is supported by several lines. Data from 632 early breast cancer (EBC) patients were collected to evaluate the influence of lifestyle factors in progression free survival (PFS) and overall survival (OS). Results of disseminated tumor cell (DTC) in bone marrow and circulating tumor cells (CTC) in blood were available as well. A complete pathological data set and medical history were obtained. It was the purpose of the present study to correlate these data to compare the findings.

Methods: We evaluated 629 bone marrow samples and 606 blood samples from EBC patients treatet between 2004 to 2010 at the time of first diagnosis. All samples underwent immunomagnetic enrichment using the AdnaTest BreastCancerSelect (AdnaGen AG, Germany) within 4 hours after blood withdrawal followed by RNA isolation and subsequent gene expression analysis by reverse transcription and Multiplex-PCR in separated tumor cells using the AdnaTest BreastCancerDetect. CTCs were analyzed for the three breast cancer associated markers: GA733-2, Muc-1, Her-2 and actin as an internal PCR control. BM aspirates were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Lifestyle data icluding menopausal status, BMI, usage of Metformin, hormone replacement drugs, beta blockers and Bisphosphonates were collected by accessing the patient files. Histological data of the primary tumor were available for each patient.

Results: The overall detection rate for CTCs was 15.41% (88/571 patients) and for DTC was 38.5% (242/628 patients), respectively. The mean BMI of 428 patients was 26.4 in 81/574 premenopausal, 426/574 postmenopausal and 67/574 perimenopausal patients. Medical history of smoking (128/394 patients), using hormone replacement therapy (92/354 patients), alcohol consumption (68/378 patients), having allergies (188/419), using Metformin (22/389 patients), taking beta blockers (83/392 patients) and Bisphosphonates (201/526 patients) were compared to PFS and OS as well as the histological data of the primary tumor.

Conclusion: Lifestyle factors seems to influence the outcome in our cohort of EBC patients as shown in previous studies. Final data and results regarding to tumor cell dissemination compared to lifestyle behaviour will be available for the SABCS 2014.

Citation Format: Bahriye Aktas, Anna Frackenpohl, Siegfried Hauch, Johann Kraus, Hans Armin Kestler, Rainer Klaus Kimmig, Sabine Kasimir-Bauer. Influence of lifestyle factors and tumor cell dissemination in 632 early 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 P6-08-39.
Abstract P6-11-03: HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies
Authors: Goka Erik T , Senderoff Dana S , Munguba Gustavo , Lippman Marc E
Published: May 2015

HER2-targeted therapies have been instrumental in improving the treatment of HER2+ breast cancer. However, drug resistance usually emerges and remains a big challenge in using anti-HER2 therapies. Previous studies have implicated activation of the Rho GTPase Rac1 by PTEN loss or IGF-1R overexpression as a mechanism of resistance to HER2-targeted therapies. We identified HACE1, an E3 ubiquitin ligase for Rac1, as a tumor suppressor capable of cooperating with HER2 to transform normal mammary epithelial cells. While HACE1 loss alone resulted in enhanced Rac activation, HER2 activation of Rac1 combined with HACE1 loss resulted in even higher levels of activated Rac resulting in the ability to form tumors in immunocompromised mice. In this study, we show that loss of HACE1 confers resistance to the HER2 tyrosine kinase inhibitor (TKI) Lapatinib due to sustained Rac signaling irrespective of EGFR/HER2 signaling. While Lapatinib inhibition alone is capable of attenuating proliferation of HER2 overexpressing mammary epithelial cells, HACE1 loss continues to drive proliferation of in vitro tumor formation (clonogenicity) as well in vivo tumor growth. We demonstrate that Lapatinib sensitivity can be restored using a Rac inhibitor in HACE1 knockdown cells. Moreover, while the Rac inhibitor alone was capable of attenuating the effects of HER2 overexpression and HACE1 loss, simultaneous inhibition of both HER2 and Rac signaling was superior to either monotherapy alone. These results support Rac activation as a mechanism of resistance to HER2-targeted therapies and highlight the use of a Rac inhibitor to treat HER2+ refractory breast cancers.

Citation Format: Erik T Goka, Dana S Senderoff, Gustavo Munguba, Marc E Lippman. HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies [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 P6-11-03.
Abstract P6-11-08: Exploring the best therapeutic partner of triple negative breast cancers: Using different characteristics/dependent pathways of triple negative breast cancer cell lines based on subgroups
Authors: Lim Bora , Dicker David T , Kline Leah C , El-Deiry Wafik S
Published: May 2015

Triple negative breast cancer (TNBC) still remains as a difficult disease given the abscence of effective treatment modality, despite some success in PARP inhibition in BRCA gene mutation patients. Recently, TNBC was elucidated to be a large group of heterogenic subgroups based on their genetic/proteomic characters. Two main subgroups that consists of greater than 90% of whole TNBC include mesenchymal like (TNMBC) and basal (TNBBC) subgroups. Mesenchymal like subgroup harbor myoepithelial, epithelial-to-mesenchymal transition related phenotype, and genetic dependency on growth hormone pathway, higher sensisitivy to death receptor inducing apoptosis pathway, as well as more dependency on PI3K-Akt-mTOR pathway. In contrast, basal like subgroup harbor the characteristics that is related to a defective DNA repair system, cell cycles regulation, and interestingly - dependency on RAS-MEK pathway for their survival and growth. Given explosive enrichment of understanding such pathways and enumeration of pathway targeting inhibitors, as well as the ability of timely recognition of biomarkers in patients sample which can differentiate subgroups of TNBC- offer an attractive strategy of novel therapeutics development in this difficult to treat disease. We tested targeting both dependent pathway and core characteristics of TNBC using representative panels of each subgroups: MDA-MB-468, BRCA1KD MCF10A, HCC1937 as in TNBBC panel showed effective killing when various combination of pAkt and PI3K, mTOR inhibitors, CDK1/2 inhibitors, death receptor mediated apoptosis inducing agents were introduced in combination. In contrast TNMBC MDA-MB-231, SUM159,BT549 showed effective killing when pERK and MEK inhibitors, in combination with BMI-1 inhibitors were given. Further elucidation of mechanisms of action in each combinations will further offer the ground of proper combination in subgroups of TNBC that could be further studied in animal model, and finally in clinical development.

Citation Format: Bora Lim, David T Dicker, Leah C Kline, Wafik S El-Deiry. Exploring the best therapeutic partner of triple negative breast cancers: Using different characteristics/dependent pathways of triple negative breast cancer cell lines based on subgroups [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 P6-11-08.
Abstract S1-07: HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer
Authors: Junttila Teemu T , Li Ji , Johnston Jennifer , Hristopoulos Maria , Clark Robyn , Ellerman Diego , Wang Bu-Er , Li Yijin , Mathieu Mary , Li Guangmin , Young Judy , Luis Elizabeth , Lewis Phillips Gail , Stefanich Eric , Spiess Cristoph , Polson Andrew , Irving Bryan , Scheer Justin M , Junttila Melissa R , Dennis Mark S , Kelley Robert , Totpal Klara , Ebens Allen
Published: May 2015

Based on recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2-TDB) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2-TDB can eliminate cells refractory to currently approved HER2 therapies. The potent anti-tumor activity of HER2-TDB was demonstrated using four model systems including MMTV-huHER2 and huCD3 transgenic mice. We demonstrate inhibitory effect of PD-L1 expression on the activity of bispecific T cell recruiting antibodies. This resistance mechanism is reversed by anti-PD-L1 treatment and combination of HER2-TDB with anti-PD-L1 immune therapy resulted in enhanced inhibition of tumor growth, increased response rates and durable responses.

Significance:

This report presents a new immunotherapy for HER2+ breast cancer with an alternative, extremely potent mechanism of action that is effective in cells resistant to current HER2 targeted therapies. Several significant advances are provided to bispecific T cell recruiting antibodies: we characterize a critical resistance mechanism, a potential diagnostic marker, a novel transgenic efficacy model and significantly improve the drug-like properties by using technology based on full length antibodies with natural architecture. Finally we demonstrate the benefit of combining two immune therapies: direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 signaling results in enhanced and durable long term responses.

Citation Format: Teemu T Junttila, Ji Li, Jennifer Johnston, Maria Hristopoulos, Robyn Clark, Diego Ellerman, Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li, Judy Young, Elizabeth Luis, Gail Lewis Phillips, Eric Stefanich, Cristoph Spiess, Andrew Polson, Bryan Irving, Justin M Scheer, Melissa R Junttila, Mark S Dennis, Robert Kelley, Klara Totpal, Allen Ebens. HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive 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 S1-07.
Abstract S2-01: Theranostic multiparametric tests improve residual risk assessment in early luminal breast cancer
Authors: Bartlett John MS , Sabine Vicky S , Haider Syed , Drake Camilla , Crozier Cheryl , Yao Cindy Q , Brookes Cassandra L , van de Velde Cornelis JH , Hasenburg Annette , Kieback Dirk G , Markopoulos Christos , Dirix Luc Y , Seynaeve Caroline , Rea Daniel W , Boutros Paul C
Published: May 2015

Background: Despite rapidly expanding availability of multiparametric tests which inform residual risk following adjuvant therapy for early breast cancer current approaches provide minimal information on the appropriate targeted therapy to be selected for patients at high risk of recurrence. We hypothesised that inclusion of key signalling nodes from driver molecular pathways in early breast cancer in residual risk signatures would both improve risk stratification and identify candidate theranostic targets for the next generation of clinical trials.

Methods: RNA was extracted from FFPE luminal breast cancers from the TEAM pathology study (Exemestane versus Tamoxifen-Exemestane). Gene expression analyses were performed for 29 genes mapped across key signalling nodes within the PIK3CA pathway. mRNA assessment for IHC4 (ER, PgR, HER2 and Ki67) was included in the model. Quantitative gene expression was performed using the Nanostring platform. Novel signatures were trained in a randomly selected sub-set of the TEAM pathology cohort (n=˜1700) and validated using the remaining 50% of patients (n=˜1700). Results presented represent those from the validation cohort.

Results: The IHC4-protein and IHC4-mRNA risk scores were highly correlated (Rho=0.72, p=4.12x10-265), suggesting the mRNA abundance-based classifier is able to serve as a good substitute for the protein-based model.

A gene signature including IHC4 markers assessed by mRNA performed significantly better (AUC 0.70 vs 0.66) than conventional IHC4. A gene signature including 4 signalling modules from the PIK3CA pathway significantly outperformed both IHC4 and the 4 gene (ER, PgR, HER2, Ki67) classifier (AUC 0.75; p = 3.23x10-7 vs IHC4 and 1.39x10-3 vs "IHC4mRNA").

Conclusions: Inclusion of PIK3CA signalling modules identified key genes/nodes which are linked to early relapse in luminal breast cancer and provided a significantly improvement in risk classification when compared to a currently validated multiparameter test.

Citation Format: John MS Bartlett, Vicky S Sabine, Syed Haider, Camilla Drake, Cheryl Crozier, Cindy Q Yao, Cassandra L Brookes, Cornelis JH van de Velde, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Caroline Seynaeve, Daniel W Rea, Paul C Boutros. Theranostic multiparametric tests improve residual risk assessment in early luminal 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 S2-01.
Abstract S6-01: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1
Authors: Hurvitz Sara A , Andre Fabrice , Jiang Zefei , Shao Zhimin , Neciosup Silvia P , Mano Max S , Tseng Ling-Min , Zhang Qingyuan , Shen Kunwei , Liu Donggeng , Dreosti Lydia M , Feng Jifeng , Burris Howard A , Toi Masakazu , Buyse Marc E , Cabaribere David , Lindsay Mary-Ann , Kunz Tiffany , Rao Shantha , Pacaud Lida B , Taran Tetiana , Slamon Dennis
Published: May 2015

Background: Everolimus (EVE), an inhibitor of mammalian target of rapamycin (mTOR), is a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. In early studies, EVE showed antitumor activity in breast cancer and synergy with both trastuzumab (TRAS) and paclitaxel. The international BOLERO-1 study is being conducted to evaluate the addition of EVE to TRAS plus paclitaxel as first-line therapy for HER2+ advanced breast cancer.

Methods: In this phase 3 randomized trial, 719 adult women with HER2+ advanced breast cancer who had not received prior TRAS or chemotherapy in the advanced setting were randomized 2:1 to receive either EVE or placebo (10 mg) in combination with weekly paclitaxel and TRAS. The two primary objectives were to compare the progression-free survivals (PFS) of everolimus/trastuzumab/paclitaxel and trastuzumab/paclitaxel/placebo in both the full population and in the Hormone Receptor negative (HR-) subpopulation. Secondary endpoints included survival, response rate, and safety. The final analysis was performed after 420 PFS events were observed in the full population.

Results: In the full population, the median age was 53 years, 70.4% had visceral metastases, 56.1% had ER and/or PgR +ve disease, and 43.3% had ≥ 3 metastatic sites. Previous adjuvant therapy included TRAS (11.4%) and taxane (24.7%).

Conclusions: The data from the final analysis will be available in October 2014. PFS, safety, and secondary efficacy endpoints will be presented at SABCS 2014. (Funded by Novartis; BOLERO-1 ClinicalTrials.gov number, NCT00876395.)

Citation Format: Sara A Hurvitz, Fabrice Andre, Zefei Jiang, Zhimin Shao, Silvia P Neciosup, Max S Mano, Ling-Min Tseng, Qingyuan Zhang, Kunwei Shen, Donggeng Liu, Lydia M Dreosti, Jifeng Feng, Howard A Burris, Masakazu Toi, Marc E Buyse, David Cabaribere, Mary-Ann Lindsay, Tiffany Kunz, Shantha Rao, Lida B Pacaud, Tetiana Taran, Dennis Slamon. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1 [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 S6-01.
Abstract A023: Investigating differential expression of microRNAs in the luminal breast cancer subtype
Authors: Ehman Dylan A. , Pinnaduwage Dushanthi , Bull Shelley B. , Andrulis Irene L.
Published: May 2015

Breast Cancer is a heterogeneous disease, and tumors vary in pathological and clinical characteristics making it important that tumors be accurately characterized at diagnosis. Current methods reveal a number of breast cancer subtypes correlating with clinical factors; however, patients with the luminal subtype have a range of outcomes. Our hypothesis is that microRNA (miRNA) expression profiling may provide a method of discriminating tumors in this subtype into good and poor prognosis groups, as well as reveal potential biological factors affecting prognosis.

Expression profiling was performed on miRNAs from 39 primary ER+, HER2- luminal breast tumors from a prospective cohort of women with node negative breast cancer with a median follow-up time of 116 months. Of the 39 tumors, 19 were from patients who eventually experienced a recurrence and 20 were from matched patients who remained disease-free. Total RNA was extracted from the specimens and the miRNAs quantified using TaqMan Array MicroRNA Cards. Results analyzed using significance analysis of microarrays (SAM) revealed nine miRNAs with a standard t-test p-value less than 0.05 and ranked within the top 20, designated as significantly differentially expressed between the two groups. Four of these, miR-135a, miR-140-5p, miR-200a, and miR-218, were selected for validation on the same samples using singleplex quantitative real-time PCR conducted in triplicate, and confirmed to be significantly less expressed in tumors in patients who had experienced recurrence compared to tumors from patients without recurrence.

Functional analysis of miR-200a and miR-218 is being performed in MCF-7 breast cancer cells to determine the role they play in luminal breast cancer recurrence. Validated targets of these miRNAs suggest involvement in epithelial to mesenchymal transition and cellular migration, invasion, and proliferation. The activity of these miRNAs is being studied in vitro and altered expression of miRNA targets is being confirmed. Future studies to examine whether these modifications result in changes in tumorgenicity phenotypes will be addressed by assaying cell proliferation, migration, and invasion.

This project has the potential to aid in improving breast cancer prognostication in the clinical setting, improve our knowledge of the role if miRNAs in luminal breast cancer, and identify miRNAs suitable as possible diagnostic biomarkers or novel therapeutic targets.

Citation Format: Dylan A. Ehman, Dushanthi Pinnaduwage, Shelley B. Bull, Irene L. Andrulis. Investigating differential expression of microRNAs in the luminal breast cancer subtype. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A023.
Abstract A035: Role of the transcription factor Id4 in the developing mammary gland
Authors: Best Sarah A. , Fu NaiYang , Vaillant Francois , Lindeman Geoff J. , Visvader Jane E.
Published: May 2015

Transcription factors are essential for controlling cell fate decisions and differentiation during embryonic and adult development. Although transcription factors have been implicated in regulating development of the mammary gland, most of these have not been defined at a cellular level. Recent studies in the laboratory have identified the transcriptional regulator Inhibitor of Differentiation 4 (Id4) as a highly expressed gene in the mammary stem cell (MaSC)-enriched population of both mouse and human mammary glands. This population also contains progenitors and mature myoepithelial cells. Germ-line deletion of Id4 in mice has previously revealed a role for this gene in neuronal differentiation1, and more recently, as a regulator of mammary gland development through its suppression of p38MAPK2. Id4 has been identified as differentially regulated in breast cancers and plays a role in the negative regulation of BRCA13,4. We have developed a conditional knockout mouse model to investigate the function of Id4 specifically in the mammary epithelium. Id4 is expressed in myoepithelial cells of the terminal end buds and ducts, with expression reducing after puberty. Consistent with previous findings2, Id4-deficient mammary glands displayed a prominent reduction in ductal elongation and branching. We found that Id4-deficient mammary epithelial cells also have a diminished capacity to maintain the balance of luminal to myoepithelial cells, and that the MaSC/basal subset had significantly reduced repopulating capacity when assayed by transplantation. Understanding the mechanism and role of Id4 in the developing mammary gland may reveal important parallels with the role of Id4 in breast cancer.

1. Yun et al. Development, 2004. 131(21):5441-8

2. Dong et al. Development, 2011. 138(23):5247-56

3. Beger et al. PNAS, 2001. 98(1):130-5

4. Roldan et al. Cancer Biology and Therapy, 2006. 5(5):505-10

Citation Format: Sarah A. Best, NaiYang Fu, Francois Vaillant, Geoff J. Lindeman, Jane E. Visvader. Role of the transcription factor Id4 in the developing mammary gland. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A035.
Abstract A036: Integrin αvβ3 drives the mammary stem cell state during pregnancy
Authors: Desgrosellier Jay , Lesperance Jacqueline , Seguin Laetitia , Shattil Sanford , Cheresh David
Published: May 2015

Epithelial stem/progenitor cell properties are associated with aggressive carcinomas. The integrin αvβ3 promotes tumor progression and metastasis in a diverse array of human carcinomas, and may be integral to epithelial stem/progenitor cell behavior. Here we reveal a critical role for αvβ3 in adult mammary stem cells (MaSCs) during pregnancy. While αvβ3 is a luminal progenitor marker in the virgin mammary gland, we noted a dramatic increase in αvβ3 expression in the MaSC pool at mid-pregnancy associated with enhanced repopulating potential. Similar to pregnancy, we noted that TGFβ, and not RANKL, was sufficient to drive αvβ3 expression enhancing MaSC activity. Accordingly, mice lacking β3 or expressing a signaling deficient form of this receptor showed defective mammary gland morphogenesis during pregnancy associated with decreased MaSC clonogenicity, expansion and outgrowth potential. Surprisingly, these mice displayed normal development of the virgin gland with no effect on luminal progenitors. These findings support a role for αvβ3 as a critical determinant of the MaSC state during pregnancy and suggest a related role for this receptor in regulating stem-like behavior in human breast cancers.

Citation Format: Jay Desgrosellier, Jacqueline Lesperance, Laetitia Seguin, Sanford Shattil, David Cheresh. Integrin αvβ3 drives the mammary stem cell state during pregnancy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A036.