bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-02-12: Predicting surgical upgrade of breast lesions detected by MRI-guided biopsy
Authors: Chen A , Brem R
Published: February 2018

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 P4-03-11: Withdrawn
Authors: Liu Q , Zhu Y , Liu Y , Li Y , Song E
Published: February 2018

This abstract was withdrawn by the authors.
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

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<0.01), S204 (p<0.01) and S213 (p<0.05) in the Smad linker region. Further, CDK2i increased expression of p15 (p<0.05) and decreased expression of c-myc (p<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

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

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.
Abstract P5-07-03: Withdrawn
Authors: Yu H , Katsaros D , Biglia N , Shen Y , Loo L , Yu X , Lin H , Fu Y , Chu W , Fei P , Ni Y , Jia W , Deng X , Qian B , Wang Z
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P5-07-05: LOC283299 suppress the lymphnode metastatic cascade in breast cancer patients
Authors: Guo R , Xue J , Su Y , Xiu B , Ji W , Chi Y , Wu J
Published: February 2018

Background

Long non-coding RNAs (lncRNAs) have been proved to play an essential role in cancer metastasis. The accuracy of intraoperative assessment of lymph nodes metastasis need to be improved. In this study, we aimed to define the lncRNA biomarker ectopic expressed in breast cancer patients' metastatic lymph nodes, and to explore the potential molecular mechanisms.

Experimental Design

RNA-seq analyses in 3 paired breast cancer patients' primary tumor and metastatic lymph node was used as training set to determine differentially expressed lncRNAs that may be associated with lymph node metastasis. The other 40 patients were analyzed as validation set to test the accuracy of lncRNAs identification by quantitative real-time PCR. The correlation between LOC283299 expression level and prognosis in other 282 breast cancer patients was confirmed. In parallel, in vitro and in vivo analyses were carried out to determine the potential mechanisms of LncRNA-dependent lymph node metastases and prognosis.

Results

RNA-seq analyses in the training set revealed significant correlation between high expression level of LOC283299 and lower lymph node metastasis potential in breast cancer patients. We further validated that the expression level of LOC283299 was significantly higher in tumor primary tissue than that in paired metastatic lymph node (P=0.0245), and higher LOC283299 expression level was markedly associated with good metastasis-free survival in breast cancer patients (P=0.04). In breast cancer cell lines, CRISPR-on overexpression of LOC283299 inhibited proliferation, migration, invasion, and metastases both in vivo and in vitro. shRNA knockdown LOC283299 promotes the ability of tumor proliferation and metastasis. The molecular mechanisms by which LOC283299 as metastasis-suppressing lncRNAs regulates recurrence and metastasis may involve regulation of epithelial to mesenchymal transition (EMT), cellular invasion and microenvironment in breast cancer cells.

Conclusion

Our study revealed a strong correlation between LOC283299 expression and lymph node metastases in breast cancers. High level of LOC283299 was associated with better metastasis-free survival. The changed metastasis phenotype may be mediated by the interaction of LOC283299 and breast cancer cells. Therefore, LOC283299 may represent a potential predictive biomarker for early lymph node metastasis in breast cancer.

Citation Format: Guo R, Xue J, Su Y, Xiu B, Ji W, Chi Y, Wu J. LOC283299 suppress the lymphnode metastatic cascade in breast cancer patients [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 P5-07-05.
Abstract P5-07-11: BHLHE40-AS1 is an enhancer associated noncoding RNA critical to breast cancer progression
Authors: DeVaux RKS , Schimjawicz H , Coarfa C , Behbod F , Herschkowitz JI
Published: February 2018

Increased emphasis on breast cancer screening has led to a dramatic increase in diagnosis of ductal carcinoma in situ (DCIS). DCIS lesions are nonobligate precursors of invasive ductal carcinoma (IDC) and thus, the current standard-of-care is aggressive therapy to prevent invasive and metastatic disease. However, only ˜40% of DCIS cases are predicted to progress leading to a current state of overtreatment and overdiagnosis. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive breast cancers and refine patient treatment strategies. We propose that long noncoding RNAs (lncRNAs) functionally drive breast cancer progression and their expression can discriminate between innocuous and potentially invasive DCIS.

Using biopsies from women with tandem DCIS and IDC lesions, we identified the lncRNA BHLHE40-AS1 as enriched in patient IDC. Furthermore, BHLHE40-AS1 is enriched in multiple breast cancer progression models, in HER2+ cell lines, and can be induced by expression of HER2. BHLHE40-AS1 is transcribed from a known super-enhancer that we find becomes rewired in breast cancer progression. In addition, the lncRNA is found antisense to BHLHE40, a transcription factor critical to many core processes (apoptosis, EMT, circadian rhythm). Depletion of the lncRNA attenuates expression of BHLHE40. Future studies are focused on mechanistically elaborating its function, its impact on the associated enhancer and chromatin looping, and determining the utility of BHLHE40-AS1 as a clinically relevant biomarker and therapeutic target in invasive breast cancer.

Citation Format: DeVaux RKS, Schimjawicz H, Coarfa C, Behbod F, Herschkowitz JI. BHLHE40-AS1 is an enhancer associated noncoding RNA critical to breast cancer progression [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 P5-07-11.
Abstract P5-12-03: Withdrawn
Authors: Wood M , Seisler DK , Hsieh M-K , Kontos D , Ambaye A , Le-Petross H , Jung S-H , Liu H , Zekan P , Cardinal L , Charlamb J , Wang LX , Unzeitig GW , Garber J , Marshall J
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P5-15-02: Withdrawn
Authors: Crew KD , Anderson G , Hershman DL , Terry MB , Tehranifar P , Lew DL , Yee M , Brown EA , Kairouz SS , Minasian LM , Ford L , Neuhouser ML , Arun BK , Brown PH
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P5-19-06: Not presented
Authors: Hardenbergh PH , Hendershott M , Giovagnoli S , Hasselbach C , Urquhart A , Nilsson RR
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-06-05: Not presented
Authors: Joukov VV , De Nicolo A , Gerson R , Chen J , Green JBA , Walter JC , Livingston DM
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-07-02: Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice
Authors: Bouamar H , Zhang F , Gu X , Dong Q , Sun L
Published: February 2018

Breast cancer is a commonly diagnosed cancer of pregnancy. However, how endogenous and exogenous endocrine factors may contribute to the development of pregnancy-associated mammary tumorigenesis is not clear. There is growing evidence that mammary stem cells (MaSCs) may initiate neoplastic transformation when dysregulated in mouse models. We investigated the effect of the environmental endocrine disruptor bisphenol A (BPA) on mouse mammary gland morphology, epithelial cell composition, pre-neoplastic lesions, and the regenerative function of MaSCs. Pregnant FVB mice with GFP transgene on Day E8.5 were implanted with osmotic pumps that constantly release BPA at 0, 25 or 250 ng/kg/day for 28 days and the mice were euthanized one month after weaning. In agreement with the literature, we observed an abnormality of the morphology of the mammary gland after BPA treatment characterized by higher duct density and abnormal secondary and tertiary branching. Quantification of percent hyperplastic mammary ducts in H&E-stained tissue slides revealed a significant increase of ducts with hyperplastic lesions after BPA treatment, particularly with the low dose. To investigate the effects of BPA treatment on MaSCs, we used enzyme digestion to isolate the CD24hi/CD49f+ luminal epithelial cells (also termed as colony forming cell or CFC) and the CD24+/CD49fhi basal epithelial cells (also termed as mammary repopulating unit or MRU) from mammary gland tissues by FACS and found no significant difference in percent of luminal or basal cell population after BPA treatment. Because the basal cells are enriched with MaSCs that can form mammospheres in suspension culture and subsequently form solid 3D organoids when cultured in Matrigel, we transplanted the solid 3D organoids into cleared mammary fat pads of syngeneic FVB mice and immune-compromised nude mice to examine how BPA treatment might alter MaSC function. Significantly, similar to the results from the primary mammary glands, the regenerated mammary glands by MaSCs from mice treated with the low dose of BPA showed increased duct density, secondary and tertiary branching, and a significantly greater number of hyperplastic lesions. Taken together, our study demonstrated that BPA exposure at very low dose could induce pre-neoplastic lesions in the mammary gland of pregnant mice, apparently by directly targeting MaSCs and implicates BPA as an exogenous endocrine factor that may promote pregnancy-associated mammary tumorigenesis.

Citation Format: Bouamar H, Zhang F, Gu X, Dong Q, Sun L. Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice [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 P6-07-02.
Abstract P6-07-03: Long non-coding RNA H19 promotes cancer stemness and worsen breast cancer survival
Authors: Shima H , Kida K , Yamada A , Sugae S , Narui K , Miyagi Y , Ryo A , Ichikawa Y , Ishikawa T , Endo I
Published: February 2018

Background: Cancer stem cells (CSC) are good sources of tumor initiation, heterogeneity, progression, and metastasis because of their unique characteristics. Several potential markers for CSCs have been suggested for breast cancer, including CD44+/CD24−/low, aldehyde dehydrogenase 1 (ALDH1), and epithelial cell adhesion molecule/epithelial-specific antigen. We previously reported that ALDH1 gene expression is related to aggressive phenotypes and poor prognosis in breast cancers. In this study, we conducted differential analysis of mRNA expression in ALDH1-positive breast cancer to identify genes associated with CSC. Next, we performed basic and clinical studies of one gene.

Methods: Messenger RNA was isolated from ALDH1-positive cells and ALDH1-negative cells in 5 ALDH1-positive breast cancers. Microarray analysis revealed that several genes were significantly associated with the ALDH1 gene. Among them, we examined a long non-coding RNA of H19 in this study. We evaluated the effect of H19 on CSCs using RNA interference and a sphere formation assay using two cell lines, HCC1937 and iCSCL10A cells. We also investigated H19 expression in 192 surgical specimens by in situ hybridization and analyzed the relationship between H19 expression and clinic pathological findings in breast cancer patients.

Results: Through in vitro experiments, we confirmed that suppression of H19 reduced sphere formation in both HCC1937 and iCSCL10A cells. Among surgical specimens, 48 samples (25%) expressed H19. We verified thatH19 positivity was significantly higher in ALDH1-positive cases than in ALDH1-negative cases (68% vs 9.7%, p < 0.001). H19 was significantly highly expressed in triple-negative breast cancer (TNBC) (46%) compared with other subtypes: luminal (33%), luminal-HER2 (6%), and HER2-enriched subtype (15%). H19-positive patients showed significantly worse prognosis (5-year disease-free survival 75.8% vs 91.5%, p = 0.001 and 5-year overall survival 88.7% vs 97.7%, p = 0.002). The effect of H19 expression on prognosis was the most significant in TNBC compared to in other subtypes (5-year disease-free survival 63.6% vs 88.9%, p = 0.038).

Conclusions: H19 is clearly associated with CSCs and correlated with poor prognosis in breast cancer patients, particularly TNBC. Our future studies will investigate the role of H19 in maintaining the nature of CSCs and protein-coding genes associated with H19.

Citation Format: Shima H, Kida K, Yamada A, Sugae S, Narui K, Miyagi Y, Ryo A, Ichikawa Y, Ishikawa T, Endo I. Long non-coding RNA H19 promotes cancer stemness and worsen breast cancer survival [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 P6-07-03.
Abstract P6-08-03: Withdrawn
Authors: Martinez ME , Tao L , San Miguel Y , Gomez S , Gago-Dominguez M , Molinolo A , Komenaka I , Schwab R
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P6-08-16: Withdrawn
Authors: Gram IT , Braaten T , Lund E , Licaj I
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P6-09-06: The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast: An analysis from the National cancer data base
Authors: Lewis GD , Xing Y , Patel T , Schwartz M , Rodriguez AA , Chen AC , Farach A , Hatch SS , Butler EB , Chang JC , Teh BS
Published: February 2018

Purpose/Objectives: Invasive micropapillary carcinoma (IMPC) is an uncommon variant of breast cancer, accounting for <2% of all cases. Previous studies demonstrated that this subtype often presents with hormone receptor (HR) positive disease, resulting in survival outcomes similar to invasive ductal carcinoma. However, many of these studies were conducted prior to the availability of HER2 testing. In this study, we aim to determine the impact of molecular marker status (including HER2 status) on survival outcomes of invasive micropapillary carcinoma.

Materials/Methods: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven IMPC diagnosed from 2007-2012. Only patients with known estrogen receptor (ER) status, progesterone receptor (PR) status and HER2 status were included in the analysis. Cox multivariate regression was used to determine prognostic factors.

Results: Overall, 865 patients met inclusion criteria. The median follow-up was 2.5 years. Out of all patients, 651 (75.3%) had HR+, HER2 negative disease, 128 (14.8%) had HR+, HER2+ disease, 41 (4.7%) had HR negative, HER2+ disease, and 45 (5.2%) had triple negative disease. Patients with triple negative disease were more likely to have poorly differentiated/undifferentiated histology (66.7%), lymphovascular invasion (73.3%), stage 3 disease (37.8%), undergone mastectomy (68.9%), and positive surgical margins (15.6%). On Cox multivariate regression, those with triple negative disease had worse overall survival (hazard ratio 7.28, P<0.001). Other prognostic factors associated with worse overall survival included African American descent (hazard ratio 2.24, P=0.018), comorbidity score of 1 (hazard ratio 2.50, P=0.011), comorbidity score ≥2 (hazard ratio 3.27, P=0.06), and ≥3 positive lymph nodes (hazard ratio 3.23, P=0.007).

Conclusions: Similar to invasive ductal carcinoma, triple negative disease in invasive micropapillary carcinoma results in worse survival outcomes. This is the largest and first study to characterize molecular status (including HER2 status) in IMPC patients, as well as its impact on survival outcomes.

Citation Format: Lewis GD, Xing Y, Patel T, Schwartz M, Rodriguez AA, Chen AC, Farach A, Hatch SS, Butler EB, Chang JC, Teh BS. The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast: An analysis from the National cancer data base [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 P6-09-06.
Abstract P6-15-01: Withdrawn
Authors: Loibl S , Untch M , Denkert C , Huober J , Blohmer JU , Grischke E-M , Furlanetto J , Tesch H , Hanusch C , Rezai M , Jackisch C , Schmitt WD , von Minckwitz G , Thomalla J , Kümmel S , Rautenberg B , Fasching PA , Rhiem K , Burchardi N , Schneeweiss A
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P6-15-10: Withdrawn
Authors: O'Connor KL , Stewart RL , Samayoa LM , Hodges KB , Romond EH , Mathew A , Weiss H , Wang C , Durbin EB , Walsh SB , Knifley T
Published: February 2018

This abstract was withdrawn by the authors.
Abstract PD4-02: Advantageous polypharmacology of abemaciclib revealed by omics profiling of CDK4/6 inhibitors
Authors: Hafner M , Mills CE , Subramanian K , Chen C , Boswell SA , Everley RA , Juric D , Sorger PK
Published: February 2018

Small molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 have created new opportunities for the treatment of advanced hormone-receptor positive (HR+) breast cancer and show promise in other malignancies. Three CDK4/6 inhibitors, palbociclib (PD0332991; Ibrance), ribociclib (LEE011; Kisqali), and abemaciclib (LY2835219), which have been approved or are in late stage trials, are reported to be broadly similar although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique adverse effects profile. Differences in pharmacokinetics and relative potency for CDK4 versus CDK6 are postulated to account for these differences. In this paper, we use molecular and functional profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors. We show that abemaciclib, but not ribociclib or palbociclib, is a potent inhibitor of kinases other than CDK4/6, including CDK1/Cyclin B, which appears to cause arrest in the G2 phase of the cell cycle, and CDK2/Cyclin E/A, which is implicated in resistance to palbociclib. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2-3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active even in retinoblastoma protein (pRb)-deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is completely ineffective. The degree of polypharmacology of small molecule drugs is increasingly viewed as an important consideration in their design, with implications for efficacy, toxicity, and acquired resistance. In the case of CDK4/6 inhibitors, we propose that abemaciclib polypharmacology elicits unique molecular responses that are likely to be therapeutically advantageous. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells. We expect such understanding to assist in stratifying patient populations and ordering sequential therapies when resistance arises.

Citation Format: Hafner M, Mills CE, Subramanian K, Chen C, Boswell SA, Everley RA, Juric D, Sorger PK. Advantageous polypharmacology of abemaciclib revealed by omics profiling of CDK4/6 inhibitors [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 PD4-02.
Abstract PD4-09: Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma
Authors: Levine KM , Chen J , Sikora MJ , Tasdemir N , Priedigkeit N , Tseng GC , Puhalla SL , Jankowitz RC , Dabbs DJ , McAuliffe PF , Lee AV , Oesterreich S
Published: February 2018

Background

Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting. Distinctive properties of ILC include growth patterns, metastatic behavior, and receptor status (almost universally estrogen receptor (ER) positive). Our lab recently generated six long-term estrogen deprivation (LTED) models of ILC cells and performed RNA-Sequencing to identify differentially expressed genes compared to their parental cells cultured with estrogen. We overlapped these results with a previously published microarray dataset and found that FGFR4 is the most consistently overexpressed gene in the setting of acquired resistance to endocrine therapy in ILC cells.

Hypothesis

FGFR4 is an important mediator of resistance to endocrine therapy in ILC.

Methods

To study the role of FGFR4 in vitro, we used multiple shRNAs and specific small molecule inhibition for growth assays of ILC cells. To study the role of FGFR4 in de novo resistance to endocrine therapy, we collected 129 well curated ER+ ILC tumor specimens and performed gene expression analysis on the pre-treatment samples using a custom NanoString panel. To study the role of FGFR4 in acquired resistance, we collected over 50 pairs of primary-metastatic ER+ tumors and performed exon capture based RNA-Sequencing.

Results

FGFR4 inhibition decreases parental and LTED ILC cell growth in classic 2D conditions, in the setting of ultra-low attachment, and in colony formation assays. The LTED cells, with higher FGFR4 expression, are more sensitive to its inhibition. For the parental cells, combination FGFR4 and ER-targeting drugs results in synergistic decreases in growth. In our database of primary ILC clinical samples, increased expression of FGFR4 is predictive of shorter time to distant recurrence. For our collection of 50 paired, primary-metastatic ER+ tissues, FGFR4 expression increases on average >2.5 fold in the metastatic setting, with large gains even in ductal carcinoma cases. Finally, in analyzing recently published cohorts of metastatic tumors, there is a significant enrichment of hotspot FGFR4 mutations in tumors originating in the breast, with >2% of metastatic ILC tumors containing such a mutation.

Conclusion

FGFR4 may play an important role in both acquired and de novo resistance to endocrine therapy in ILC.

Citation Format: Levine KM, Chen J, Sikora MJ, Tasdemir N, Priedigkeit N, Tseng GC, Puhalla SL, Jankowitz RC, Dabbs DJ, McAuliffe PF, Lee AV, Oesterreich S. Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma [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 PD4-09.
Abstract PD5-08: Not presented
Authors: Bardia A , Kabos P , Wilks S , Richards D , Harb W , Elledge R , Wang D , Jiang H , Garner F , O'Neill A , Kaklamani V
Published: February 2018

This abstract was not presented at the symposium.
Abstract PD6-04: Not presented
Authors: Barberio MT , Thomas S , Ali N , Park J , Rosenblum MD , Budillon A , Pawlowska N , Munster PN
Published: February 2018

This abstract was not presented at the symposium.
Abstract PD8-11: APOBEC3 contributes to mutational load in breast cancer
Authors: Zhao W , Peng Y , Mills GB , Peng G
Published: February 2018

Breast cancer results in large part from the accumulation of multiple mutations in premalignant cells, which provide a molecular basis for genetic diversity. This genetic diversity in premalignant cells allows selection for increased proliferation and survival and ultimately leads to invasion, metastasis, and therapeutic resistance. Recent genome-wide sequencing data showed that APOBEC3B (A3B) contributes to mutational load in breast cancer. A3B, a DNA cytosine deaminase, is overexpressed in more than 50% of breast tumors and more than 75% of breast cancer cell lines. Its overexpression and aberrant activation lead to unexpected clusters of mutations in the majority of breast cancers. This phenomenon of clustered mutations, termed kataegis (shower in Greek) forms a unique mutation signature in breast cancer. On the basis of the finding that A3B is a key molecular determinant of the mutator phenotype in breast cancer, the goal of our research is to utilize informatics tools to systematically characterize genetic alterations of APOBEC3 family proteins in breast cancer genomic data and define the molecular impact of altered APOBEC3 family proteins on mutability and anti-tumor immunity.

Our data showed that the mutation rate and copy number amplification/deletion of APOBEC3 genes are low. The levels of APOBEC3A (A3A) and A3B are highly correlated and are highest in Basal subtype and lowest in Luminal A tumors, in concordance with the proliferation of subtypes. Additionally, A3A and A3B are significantly correlated with total mutational load as well as with TP53 mutation, and with somatic copy number alterations (SCNA), especially focal SCNA. Among APOBEC3 genes, A3B is significantly associated DNA replication, DNA damage repair, cell cycle and proteasome signatures, and shows predictive and prognostic capacity in ER-positive patients. Interestingly, A3G expression is strongly associated with immune response signature genes in all breast tumors. Consequently, A3G is highly associated with tumor-infiltrating lymphocytes in breast and several other disease types.

In summary, our data demonstrate distinct expression pattern of APOBEC3 genes in different breast cancer subpopulations. Overexpression of different APOBEC3 family members leads to distinct molecular consequences. These data provide new molecular insights into pathophysiological functions of APOBEC3 genes in breast cancer and provide therapeutic opportunities for the breast cancer patients whose tumors have altered APOBEC3 expression levels and potentially are driven by APOBEC3 genes. Importantly, APOBEC3G is associated with evidence of immune activation that may signal responsiveness to immune checkpoint inhibitors.

Citation Format: Zhao W, Peng Y, Mills GB, Peng G. APOBEC3 contributes to mutational load 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 PD8-11.
Severe Adverse Reaction to Vemurafenib in a Pregnant Woman with Metastatic Melanoma
Authors: de Haan Jorine , van Thienen Johannes V. , Casaer Michael , Hannivoort Rebekka A. , Van Calsteren Kristel , van Tuyl Minke , van Gerwen Mathilde M. , Debeer Anne , Amant Frédéric , Painter Rebecca C.
Published: February 2018

Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.
Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy
Authors: Zhao Qingdong , Ye Mingxia , Yang Wen , Wang Min , Li Mingxia , Gu Chenglei , Zhao Luyang , Zhang Zhe , Han Weidong , Fan Wensheng , Meng Yuanguang
Published: February 2018

Background/Aims: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results: First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular oxidative stress, energy metabolism and calcium overload. Through excessive mitochondrial fission and aberrant mitophagy, Mst1 launched caspase 9-related mitochondrial apoptosis and abrogated F-actin/lamellipodium-dependent cellular migration. Notably, we also defined NR4A/miR181c as the upstream signal for Mst1 dysfunction in endometriosis. Conclusion: Collectively, our results comprehensively described the important role of the NR4A-miR181c-Mst1 pathway in endometriosis, which handled mitochondrial apoptosis and F-actin/ lamellipodium-based migration via the regulation of Drp1-related mitochondrial fission and Parkin-required mitophagy, with a potential application in endometriosis therapy by limiting ESCs migration and promoting apoptosis.
High-Sensitivity Cardiac Troponin I and the Diagnosis of Coronary Artery Disease in Patients With Suspected Angina Pectoris
Authors: Adamson Philip D. , Hunter Amanda , Madsen Debbie M. , Shah Anoop S.V. , McAllister David A. , Pawade Tania A. , Williams Michelle C. , Berry Colin , Boon Nicholas A. , Flather Marcus , Forbes John , McLean Scott , Roditi Giles , Timmis Adam D. , van Beek Edwin J.R. , Dweck Marc R. , Mickley Hans , Mills Nicholas L. , Newby David E.
Published: February 2018

Background:

We determined whether high-sensitivity cardiac troponin I can improve the estimation of the pretest probability for obstructive coronary artery disease (CAD) in patients with suspected stable angina.

Methods and Results:

In a prespecified substudy of the SCOT-HEART trial (Scottish Computed Tomography of the Heart), plasma cardiac troponin was measured using a high-sensitivity single-molecule counting assay in 943 adults with suspected stable angina who had undergone coronary computed tomographic angiography. Rates of obstructive CAD were compared with the pretest probability determined by the CAD Consortium risk model with and without cardiac troponin concentrations. External validation was undertaken in an independent study population from Denmark comprising 487 patients with suspected stable angina. Higher cardiac troponin concentrations were associated with obstructive CAD with a 5-fold increase across quintiles (9%–48%;
P
<0.001) independent of known cardiovascular risk factors (odds ratio, 1.35; 95% confidence interval, 1.25–1.46 per doubling of troponin). Cardiac troponin concentrations improved the discrimination and calibration of the CAD Consortium model for identifying obstructive CAD (C statistic, 0.788–0.800;
P
=0.004; χ
2
=16.8 [
P
=0.032] to 14.3 [
P
=0.074]). The updated model also improved classification of the American College of Cardiology/American Heart Association pretest probability risk categories (net reclassification improvement, 0.062; 95% confidence interval, 0.035–0.089). The revised model achieved similar improvements in discrimination and calibration when applied in the external validation cohort.

Conclusions:

High-sensitivity cardiac troponin I concentration is an independent predictor of obstructive CAD in patients with suspected stable angina. Use of this test may improve the selection of patients for further investigation and treatment.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01149590.
Diabetic Cardiomyopathy
Authors: Jia Guanghong , Hill Michael A. , Sowers James R.
Published: February 2018

Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin–angiotensin–aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
Status of Hypertension in China
Authors: Wang Zengwu , Chen Zuo , Zhang Linfeng , Wang Xin , Hao Guang , Zhang Zugui , Shao Lan , Tian Ye , Dong Ying , Zheng Congyi , Wang Jiali , Zhu Manlu , Weintraub William S. , Gao Runlin ,   On behalf of the China Hypertension Survey Investigators*
Published: February 2018

Background:

Although the prevalence of hypertension (HTN) continues to increase in developing countries, including China, recent data are lacking. A nationwide survey was conducted from October 2012 to December 2015 to assess the prevalence of HTN in China.

Methods:

A stratified multistage random sampling method was used to obtain a nationally representative sample of 451 755 residents ≥18 years of age from 31 provinces in mainland China from October 2012 to December 2015. Blood pressure (BP) was measured after resting for 5 minutes by trained staff using a validated oscillometric BP monitor. HTN was defined as systolic BP (SBP) ≥140 mm Hg/or diastolic BP (DBP) ≥90 mm Hg or use of antihypertensive medication within 2 weeks. Pre-HTN was defined as SBP 120 to 139 mm Hg and DBP 80 to 89 mm Hg without antihypertensive medication. HTN control was defined as SBP <140 mm Hg and DBP<90 mm Hg. In addition, the prevalence of HTN (SBP ≥130 or DBP ≥80 mm Hg) and control rate (SBP <130 and DBP <80 mm Hg) of HTN were also estimated according to the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline.

Results:

Overall, 23.2% (≈244.5 million) of the Chinese adult population ≥18 years of age had HTN, and another 41.3% (≈435.3 million) had pre-HTN according to the Chinese guideline. There were no significant differences of HTN prevalence between urban and rural residents (23.4% versus 23.1%,
P
=0.819). Among individuals with HTN, 46.9% were aware of their condition, 40.7% were taking prescribed antihypertensive medications, and 15.3% had controlled HTN. Calcium channel blockers were the most commonly used antihypertensive medication (46.5%) as monotherapy, and 31.7% of treated hypertensive patients used ≥2 medications. The prevalence of HTN based on the 2017 American College of Cardiology/American Heart Association guideline was twice as high as that based on 2010 Chinese guideline (46.4%), whereas the control rate fell to 3.0%.

Conclusions:

In China, there is a high prevalence of HTN and pre-HTN, and awareness, treatment, and control of HTN were low. Management of medical therapy for HTN needs to improve.