bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-08-02: Novel tumor suppressor regulating the PI3K/AKT pathway in breast cancer
Authors: Chan S , Cardamone MD , Perissi V 
Published: February 2018

Abstract
Breast cancer affects approximately 1 in 8 women over the course of their lifetime. Of the many genes and pathways deregulated by this heterogeneous disease, alterations of members in the PI3K/AKT pathway are present in approximately 20% of all cases, making it one of the more frequently mutated pathways in breast cancer. The PI3K/AKT pathway is well known to be involved in essential cellular processes necessary for cancer development and progression, including altered proliferation, metabolism, and cell survival. Previous studies have made it well known that the activation of AKT is regulated through its phosphorylation, but recent studies have also shown that AKT can also be regulated via ubiquitination, leading to AKT hyperactivation. However, the mechanism and players involved in this process are not well understood. Better understanding of these pathways could inform on better potential therapeutics to target this disease.
Recent work in our lab has identified GPS2, a member of the NCoR/SMRT complex, as a regulator of the insulin-signaling pathway through the inhibition of AKT ubiquitination by Ubc13. As many human cancers frequently have an increase in activated AKT, here we explore the potential of GPS2 as a tumor suppressor in the context of breast cancer and hope to elucidate the mechanism by which AKT ubiquitination regulates its activation.
Citation Format: Chan S, Cardamone MD, Perissi V. Novel tumor suppressor regulating the PI3K/AKT pathway in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-02.
Abstract P2-10-11: A microRNA signature associated with pathological complete response to a novel neoadjuvant therapy regimen in triple negative breast cancer
Authors: Vázquez RG , Camarillo CL , Marchau LM , García ER , Miranda AA , Martínez HM , Parra AC , De la Vega HA , Barrios AG , Cuevas SR 
Published: February 2018

Abstract
Background: Locally advanced triple negative breast cancer (laTNBC) patient's exhibits resistance to neoadjuvant chemotherapy (NC) and poor survival. Distinct therapeutic combinations have been used to reduce high mortality. Recently, novel regimens of NC for laTNBC have achieved pathological complete response (pCR) rates of 10-50%. Evaluation of pCR during oncologic treatment is decisive to identify those patients that response or not response to NC. MicroRNAs (miRNAs) are small non-coding RNAs that represent novel and potential predictive biomarkers useful to identify the patients who will get pCR in cancer.
Methods: Thirty-five patients diagnosed with laTNBC, were invited to participate in this study and enrolled after they signed an informed consent. The 22 patients with pCR and 13 patients without pCR received the experimental NC fluorouracil, adriamycin, cyclophosphamide, cisplatin, paclitaxel (FAC--CDDP/paclitaxel). MiRNA expression profiling was evaluated for 754 miRNAs. A discovery cohort (n=10 pCR and n=8 no-pCR) and a validation cohort (n=12 pCR and n=5 no-pCR). Bioinformatics analysis revealed the affected cellular pathways in pCR group. After a median clinical follow-up of 60 months, statistical analysis was performed to identify miRNAs that could discriminate pCR from no-pCR by using FAC--CDDP/paclitaxel.
Results: MiRNAs expression profiling identified 11 miRNAs that showed significant differences between pCR and no-pCR (p&lt;0.05 and fold change &gt;1.5) groups. Eight miRNAs (miR-9-3p, -30a-3p, -135b, -135b*, -380-5p, -941, -652 and miR-181c*) were upregulated and three miRNAs (miR-770-5p, -584 and miR-143) were downregulated in pCR patients. The altered cellular pathways for the set of miRNAs were PI3K/AKT, FoxO, Ras and ERBB (p&lt;0.05). Four differentially expressed miRNAs (miR-770-5p, miR-143-5p, miR-30a-3p, miR-9-3p) were confirmed in the validation phase. Expression of these miRNAs above the median level was a significant predictor of pCR to experimental NC in laTNBC patients (p&lt;0.001).
Conclusions: These four validated miRNAs could be used as predictors of pCR in response to FAC---CDDP/Paclitaxel treatment in laTNBC patients.
Citation Format: Vázquez RG, Camarillo CL, Marchau LM, García ER, Miranda AA, Martínez HM, Parra AC, De la Vega HA, Barrios AG, Cuevas SR. A microRNA signature associated with pathological complete response to a novel neoadjuvant therapy regimen in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-11.
Abstract P2-11-08: Risk factors for fibrosis after whole breast radiation therapy in lateral position : A large scale single center experience
Authors: Bronsart E , Dureau S , Xu HP , Costa E , Poortmans P , Chilles A , Berger F , Stilhart A , Fourquet A , Kirova Y 
Published: February 2018

Abstract
Background and Purpose: We previously confirmed the efficacy and safety of our technique of whole breast radiation therapy (WBRT) in isocentric lateral decubitus (ILD) position. The purpose of this work is to evaluate the risk factors for long-term fibrosis in patients treated in ILD position.
Material and methods: We studies 832 consecutive female patients with early stage BC treated by conservative surgery followed by 3D-conformal WBRT at Institut Curie between 2005 and 2010. Fibrosis and deformation were evaluated at the end of the treatment and subsequently every 6 months during at least 5 years, using NCI CTC v3.0 scale. Different fractionation schedules were used: 66Gy in 33 fractions, 50Gy in 25 fractions, 40Gy in 15 fractions, 41.6Gy in 13 fractions and 30Gy in 5 weekly fractions.
Results: Median age is 61.5 years (range: 29 - 90); median follow up is 6.4 years (range: 1.5 - 12.4). During the follow-up, 308 patients (38.9%) had grade 1 fibrosis, and 36 patients (4.3%) only, had grade 2-3 fibrosis. Among patients with grade 1 to 3 fibrosis, the median time to development of fibrosis was 1.6 years (range: 9 days – 8.3 years). In univariate and multivariate analysis, age, cup size and chemotherapy administration had no significant influence on development of breast fibrosis. The hypo fractionated schedule of 30Gy in 5 fractions significantly increased the fibrosis rate (OR=12.5; [2.7; 57.1] p=0.001). On the other hand, 40 Gy/15 fr and 41.6 Gy/13 fr had no significative influence (OR=2.2 [0.5; 11.1] p=0.32) as well as the 66 Gy/33 fr schedule (OR=3.6 [0.8; 15.4] p=0.09) compared to standard scheme of 50 Gy/25 fr. The cosmetic result was good or excellent for 84.8% of cases at the first evaluation. The 30 Gy in 5 fractions schedule significantly influenced the cosmetic result in the multivariate analysis (OR=11.2 [3.1; 43.9]; p&lt;0.001), with increased rates of breast deformation. The risk of breast deformity was also worse for large breast size (OR=2.7 [1.3; 5.8]; p=0.02).
Conclusion: Whole breast radiation therapy in ILD position is well tolerated with good cosmesis and low rates of fibrosis, except for the 30 Gy in 5 weekly fractions schedule. Large breast size has a significantly negative influence on cosmetic results and fibrosis.
Citation Format: Bronsart E, Dureau S, Xu HP, Costa E, Poortmans P, Chilles A, Berger F, Stilhart A, Fourquet A, Kirova Y. Risk factors for fibrosis after whole breast radiation therapy in lateral position : A large scale single center experience [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-08.
Abstract P3-14-09: Low rates of chronic breast cancer related lymphedema (BCRL) in a cohort of high-Risk patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS)
Authors: Kaufman D , Shah C , Vicini F 
Published: February 2018

Abstract
Background: We report outcomes using prospective BIS surveillance in a high-risk cohort of patients who all underwent axillary lymph node dissection (ALND).
Methods: From 8/2010 through 12/2016, 206 consecutive patients were evaluated with BIS as part of a prospective surveillance program. 30 underwent ALND and constitute the study population. The program included pre-operative BIS measurement as well as post-operative assessments at regular intervals. Patients with L-Dex readings increasing by more than 10 from baseline were considered to have subclinical BCRL and treated with an over-the-counter (OTC) compression sleeve for 4 weeks. For the purpose of this analysis, additional high-risk features were defined as receipt of axillary radiation, a high body mass index (BMI) or the use of taxane based chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy (CDP).
Results: Median follow-up was 36 months (range: 4.8-122.1 months). The median number of nodes removed was 18 (range: 5-32) and the median number of positive nodes was two. The median age for the cohort was 57.5 years old with 70% of patients undergoing mastectomy and the remainder breast conserving therapy. With respect to additional high-risk features, 77% also received taxane-based chemotherapy, 62% axillary irradiation, and 48% had an elevated BMI. Overall, 86% of patients had at least one additional high-risk feature, 70% at least two, and 23% had all three additional high-risk features. Seven patients (23%) had an elevated L-Dex score at some point during follow-up and underwent intervention with an OTC sleeve for 4 weeks. To date, no patients have required CDP at any time.
Conclusions: Prospective surveillance with BIS in a high-risk cohort of patients all undergoing ALND (plus additional high-risk features) led to no patients requiring CDP. These excellent findings are consistent with growing data supporting the use of BIS in prospective BCRL surveillance programs.
Citation Format: Kaufman D, Shah C, Vicini F. Low rates of chronic breast cancer related lymphedema (BCRL) in a cohort of high-Risk patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-09.
Abstract P4-02-12: Predicting surgical upgrade of breast lesions detected by MRI-guided biopsy
Authors: Chen A , Brem R 
Published: February 2018

Abstract
Background:
Patients who have suspicious breast lesions identified with MRI without mammographic- or ultrasound-correlated biopsy require MRI-guided biopsy. However, MRI-guided biopsy may underestimate the pathology due to intrinsic heterogeneity, in which subsequent surgical excision may reveal an upgrade. The reported upgrade rate is variable across studies, subclasses of lesion, and needle gauge, and no associative factors have been identified. This study investigated demographic and histologic characteristics of lesions that underwent MRI-guided biopsy to determine possible factors for predicting later upgrade at surgery.
Methods:
All MRI-guided vacuum biopsies performed between 2012 and 2017 at GWU Breast Imaging Center were reviewed. Surgical excision was performed for high risk lesions and imaging discordance in benign lesions. Variables investigated include patient age, menopausal status, personal/family history of breast cancer and breast pathology. T-test and Pearson's chi-squared test were used to determine statistical significance (alpha=0.05).
Results:
Of 379 lesions from 295 patients that underwent MRI-guided biopsy, 117 lesions from 96 patients underwent subsequent surgical excision. Pathology of the 117 lesions included benign (14/117; 12%), ALH (17/117; 15%), LCIS (10/117; 9%), ADH (10/117; 9%), papilloma (25/117; 21%), radial scar (12/117; 10%), DCIS (13/117; 11%), invasive cancer (10/117; 9%), and others (6/117; 5%). 14 of 117 lesions (12%) were upgraded at surgery: 5 upgraded from benign to high-risk, 1 upgraded from benign to DCIS, 4 upgraded from high risk to DCIS, 1 upgraded from high risk to invasive cancer and 3 upgraded from DCIS to invasive cancer. All 14 patient with upgrades (100%) had a personal history of breast cancer. No association was found with age, menopausal status, breast pathology, or family history.
Conclusions:
Our study demonstrated a surgical upgrade rate of 12%. All upgrades occurred in women with a personal history. We suggest that patients with a personal history of breast cancer pose a higher risk of surgical upgrade at excision.
Citation Format: Chen A, Brem R. Predicting surgical upgrade of breast lesions detected by MRI-guided biopsy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-12.
Abstract P4-03-16: Cyclin E affects Smad3 pathway in trastuzumab resistant HER2+ breast cancer
Authors: Decker JT , Wan L , Shea LD , Jeruss JS 
Published: February 2018

Abstract
Introduction and Objective: HER2 amplification is found in approximately 20% of patients with breast cancer and is associated with poor prognosis. Trastuzumab, a humanized anit-HER2 antibody, has been shown to improve patient outcomes, but clinical efficacy for this treatment is limited by the high rate of drug resistance. Cyclin E overexpression and cyclin-dependent kinase 2 (CDK2) activation correlate with trastuzumab resistance, and the underlying mechanisms of this correlation are an area of active study. In this work, we examined the contribution of cyclin E/CDK2-mediated Smad3 noncanonical phosphorylation to trastuzumab resistance in HER2+ breast cancer.
Methods: Trastuzumab resistant BT474R2 cells were developed by culturing BT474 cells in trastuzumab-supplemented media for 18 months. These cells were then inoculated into immunodeficient mice and treated with trastuzumab twice weekly. BT474 and BT474R2 cells were used to study cell proliferation, phosphorylation in the Smad3 linker region and transcription factor activities with a living cell array.
Results: Inhibition of cyclin E activity with CDK2 inhibitor therapy (CDK2i, 600 nM) significantly decreased BT474R2 cell proliferation. CDK2i treatment led to decreased phosphorylation at T179 (p&lt;0.01), S204 (p&lt;0.01) and S213 (p&lt;0.05) in the Smad linker region. Further, CDK2i increased expression of p15 (p&lt;0.05) and decreased expression of c-myc (p&lt;0.05) in comparison with trastuzumab treatment. Transduction of BT474R2 cells with a 5M Smad3 construct containing inhibitory mutations in 5 CDK2 phosphorylation sites resulted in decreased cell proliferation. In a transfected cell array using BT474 and BT474R2 cells, activities of cell proliferation and metastasis-associated transcription factors were significantly different between the trastuzumab sensitive and resistant cells.
Conclusions: Taken together, overexpression of cyclin E leads to Smad3 noncanonical phosphorylation and results in trastuzumab resistance in HER2+ breast cancer. CDK2i treatment may be a promising therapeutic strategy for patients with trastuzumab resistance.
Citation Format: Decker JT, Wan L, Shea LD, Jeruss JS. Cyclin E affects Smad3 pathway in trastuzumab resistant HER2+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-16.
Abstract P4-04-14: Anti-tumor activity of elacestrant (RAD1901) in combination with alpelisib (BYL-719) in patient-derived xenograft models of ER+ breast cancer
Authors: Sankaran B , Garner F , Hattersley G , Purandare D , Bihani T 
Published: February 2018

Abstract
Estrogen-receptor positive (ER+) breast cancers make up approximately 70% of all breast cancers diagnosed. While patients with ER+ breast cancer have a better prognosis than other subtypes of breast cancer, the majority of those with advanced metastatic disease will eventually relapse. This has been attributed, in part, to mutations in the ER gene that result in constitutive activation of ER and contribute to aromatase inhibitor treatment resistance. As a strategy to deliver a more durable response in this setting, the use of selective estrogen receptor degraders (SERDs) that target and inhibit both wild-type and mutant ER has gained widespread attention. Indeed, fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable selective estrogen receptor degrader (SERD) as an inhibitor of ER+ breast cancer growth in preclinical models, including those that harbor ER mutations and those that are insensitive to fulvestrant. In addition to ER mutations, the activation of parallel oncogenic pathways can also drive endocrine resistance, with the PI3K/Akt/mTOR pathway chief among those driving growth and treatment resistance to endocrine therapy. Consistent with these above-mentioned findings, recent clinical strategies to treat advanced ER+ disease have involved combining SERDs with PI3K inhibitors. Alpelisib (BYL-719) is a PI3K-alpha specific inhibitor that is being developed in combination with endocrine agents for the treatment of ER+ breast cancer. Here, we examined the effect of elacestrant in combination with alpelisib, in two ER+ breast cancer PDX models (one harboring wild-type ER and one harboring a Y537S mutation in the ER gene). The combination of elacestrant (10mg/kg) and alpelisib (35mg/kg) was well tolerated and resulted in significant tumor growth inhibition in both PDX models. Interestingly, in the mutant ER PDX model, the combination resulted in significantly greater growth inhibition relative to either compound alone. These data suggest the dual inhibition of the ER and PI3K signaling pathways with elacestrant and alpelisib produces significant anti-tumor activity in clinically-relevant PDX models, including those harboring ER mutations.
Citation Format: Sankaran B, Garner F, Hattersley G, Purandare D, Bihani T. Anti-tumor activity of elacestrant (RAD1901) in combination with alpelisib (BYL-719) in patient-derived xenograft models of ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-14.
Abstract P4-06-17: Expanded panel testing in patients with breast or ovarian cancer in a rural familial cancer program
Authors: Hermel DJ , McKinnon WC , Colello L , Greenblatt MS , Wood ME 
Published: February 2018

Abstract
Objective: We sought to investigate our center's experience with multi-gene panel testing in breast and ovarian cancer patients from a largely rural catchment area. Our goal was to identify predictors of pathogenic variants and assess indicators for expanded genetic testing.
Methods: We conducted a retrospective review of breast and ovarian cancer patients who underwent panel testing between May 2011 and April 2016. A variety of commercial gene panels were used with variant classification determined by the individual laboratory. Differences in patient demographics, age of first cancer diagnosis, number of genes tested and tumor characteristics including hormone/HER2 status, histology, differentiation, tumor size and AJCC staging classification were analyzed among pathogenic variant positive, negative, and VUS patient subsets with a chi-square test and one-way ANOVA.
Results: We identified 215 patients who underwent panel testing: the average age of patients was 52.9 ± 12 with first cancer onset at 47 ± 12; 27% of patients had undergone prior single-gene testing; 7% of patients had ovarian cancer and 93% of patients had breast cancer. VUS were detected in 18.1% of patients and pathogenic variants were detected in 9.3% of patients. Of the 20 pathogenic variants identified, 1 was detected in BARD1, 2 in BRIP1, 3 in MUTYH, 5 in CHECK2, 2 in BRCA1, 2 in BRCA2, 3 in ATM, 1 in PALB2 and 1 in PMS2. In our breast cancer cohort, there was a statistical difference (p=.03) between patients with VUS, pathogenic variants and negative testing in respect to hormone and HER2 status. Most pathogenic variants (75%) were in patients who were HER2 negative, with the majority of VUS detected in patients who were hormone receptor positive (66%). Between the groups, there were no differences in histology, tumor differentiation, size or AJCC stage classification. However, individuals with pathogenic variants tended to have a younger age of first cancer diagnosis, have higher grade disease and have triple negative tumors.
Conclusions: Specific tumor patterns (that is, HER2 negative or triple negative pathology) may be important indicators for genetic testing in breast cancer patients. Expanded panel testing should be considered in patients with a younger age of cancer diagnosis, higher grade disease and triple negative tumors.
Citation Format: Hermel DJ, McKinnon WC, Colello L, Greenblatt MS, Wood ME. Expanded panel testing in patients with breast or ovarian cancer in a rural familial cancer program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-17.