bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-12-16: Five year outcomes of a prospective study of proton radiotherapy for breast cancer regional nodal irradiation
Authors: Bradley JA , Dagan R , Liang X , Ho MW , Rutenberg M , Mailhot R , Morris C , Mendenhall NP
Published: May 2019

Purpose: Through improved nodal coverage and decreased dose to the heart and lung, proton therapy (PT) may improve the therapeutic ratio for treatment of breast cancer requiring regional nodal irradiation (RNI). The purpose of this study is to report 5 year disease control and toxicity.

Methods: From May 2012 to February 2014, 18 women (stage IIA-IIIB) prospectively enrolled on a pilot study. Median age was 52 years (range, 42-73), with equal division between breast-conserving therapy (BCT) and mastectomy and right and left-sided cancers. Median number of positive nodes among the 16 node-positive patients was 2 (range, 1-14). Five patients had ≥ 10 nodes positive on axillary dissection (N3a). Treatment targets (CTVs for breast/chest wall, supraclavicular, axillary, internal mammary nodes (IMNs)) and organs at risk were delineated on CT scans. Double scatter PT alone was used for 10 patients (9 post-mastectomy, 1 after BCT) and combined proton-photon in 8 (all BCT). Toxicity was prospectively recorded using CTCAE v4.0.

Results: Median follow-up was 4 years (range, 0.3 – 6). 5 year overall survival was 82% and locoregional control was 100%. 5 year distant metastases-free survival was 82%.

No grade 4+ toxicity developed. Four patients developed grade 3 cellulitis, which was the only grade 3 toxicity. One patient had a reconstructive failure associated with a post-surgical cellulitis. A right-sided patient was diagnosed with CHF within 2 months of completion of PT, following diagnosis of a pulmonary embolus 1 month prior. She had an elevated BNP (1101) prior to PT following adriamycin-based chemotherapy. Mean heart dose was 0 Gy and cardiac V5 0%. Atrial fibrillation developed in two patients. One patient developed grade 2 pneumonitis (she received concurrent chemotherapy). One patient, with a history of rib fractures prior to PT, developed an ipsilateral rib fracture 7 months after PT.

Conclusion: In a population of women with locally advanced breast cancer, PT for RNI has proven feasible after either mastectomy (with or without reconstruction) or BCT with excellent locoregional control. PT allows for highly conformal radiation delivery without compromise of target coverage or excess exposure of normal tissue. Documentation of the ultimate benefits of PT in this population, freedom from radiation induced cardiac disease and breast cancer recurrence will require prospective study of a larger numbers of patients.

Citation Format: Bradley JA, Dagan R, Liang X, Ho MW, Rutenberg M, Mailhot R, Morris C, Mendenhall NP. Five year outcomes of a prospective study of proton radiotherapy for breast cancer regional nodal irradiation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-16.
Abstract P3-12-19: Withdrawn
Authors: Chowdhary M , Lee A , Gao S , Barry PN , Diaz R , Decker RH , Wilson LD , Evans SB , Moran MS , Knowlton CA , Patel KR
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Chowdhary M, Lee A, Gao S, Barry PN, Diaz R, Decker RH, Wilson LD, Evans SB, Moran MS, Knowlton CA, Patel KR. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-19.
Abstract P3-14-06: Concordance assessment of IBM Watson for Oncology with MDT in patients with breast cancer
Authors: Xu J , Sun T , Hua S
Published: May 2019

Objective: IBM Watson for Oncology (WFO) is an artificial intelligence cognitive clinical decision support system which provides evidence-based treatment recommendations in cancer. This study aimed to examine the level of agreement (concordance) between treatment recommendations made by WFO and a multidisciplinary tumor (MDT) board for adjuvant therapy in early stage breast cancer and first-line therapy in metastatic breast cancer.

Methods: Treatment recommendations were provided by WFO and MDT board for 92 early stage and 40 metastatic breast cancer cases between Jan 2017 and Jan 2018. WFO treatment recommendations were provided in 3 categories: “Recommended”, “For Consideration” and “Not Recommended.” It was considered concordant if the tumor board recommendations were designated 'recommended' or 'for consideration' by WFO Version 17.10.

Results: Overall treatment concordance between WFO and MDT was 76.51%, 73 cases with early stage breast cancer (79.35%) and 28 cases with metastatic breast cancer (70.00%) we concordant. Among all the 132 cases, 49 cases were in 'Recommended' category, 52 cases were in 'for consideration' category, and 26 cases were disconcordant. Subgroup analysis found that patients with stageIIIdisease or triple-negative breast cancer were the most likely to be concordant. Luminal A type and HER2-positive cases were less likely to be concordant than other types. In early stage breast cancer, based on the low recurrence risk, 11 cases and 2 cases were treated with TC and EC regimen instead of AC-T or CMF regimen recommended by WFO. 4 patients with HER2-positive were disconcordance by using TCbH or AC-TH regimen instead of AC-TH or CMFH regimen recommended by WFO. The main reason of disconcordance in metastatic cancer was that CDK4/6 inhibitors had not been approved in China.

Conclusion: Treatment recommendations made by WFO and the tumor board showed highly concordant in breast cancer. Cancer stage and subtype had significant influence on concordance, and Watson for Oncology need to be optimized in localization.

Citation Format: Xu J, Sun T, Hua S. Concordance assessment of IBM Watson for Oncology with MDT in patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-06.
Abstract P3-14-10: Intralesional steroid injection: A novel method to treat the symptoms of idiopathic granulomatous mastitis
Authors: Manst DJ , Ganschow PS , Marcus EA , Holden C , Datta S
Published: May 2019

Background: Idiopathic granulomatous mastitis (IGM) is a chronic, inflammatory breast condition of benign nature that can clinically mimic breast cancer. Patients frequently present with a large, painful breast mass with associated inflammatory changes of the skin, and possible ulceration or fistula of the breast. Attempted methods for symptomatic relief include surgical excision and medical therapies including oral corticosteroids. Due to the success of treating dermatologic conditions with intralesional steroid injections, it was hypothesized that injecting the subdermal lesions of IGM may benefit patients with this disease. The use of intralesional steroid injections for the treatment of IGM has not been previously described in the literature.

Methods: Retrospective chart review was performed on a series of four patients with IGM who received intralesional steroid injections between August 2017 and April 2018. Patients were selected for treatment with injections based on their subjective report of painful breast lesions, lesion characteristics including size and depth, and the patient's desire to stop oral steroid therapy due to side effects despite active or residual disease. Data were collected on demographics, initial physical examination findings, prior and current treatments, characteristics of disease, details of injections performed, objective and subjective response to treatment, and recurrence.

Results: All patients presented with breast pain and either a mass, swelling, or hardness of the breast. Each patient received between one and three injection treatments, with one to four lesions treated in each session. Patients demonstrated improvement in subjective and objective symptoms after 87.5% of injection sessions (7 out of 8) by the subsequent follow-up visit (21-34 days). During the study period, three patients experienced resolution of at least one breast lesion within about 2 months (31-139 days, mean 68 days) without recurrence. One patient had four breast lesions that completely resolved (35-217 days, mean 88 days), but three of them recurred (63-217 days, mean 149 days).

Conclusion: In a small group of patients with idiopathic granulomatous mastitis, intralesional steroid injections were associated with an improvement in both subjective symptomatic relief and objective breast lesion characteristics in most cases. This treatment was associated with a good rate of lesion resolution and a low short-term recurrence rate.

Citation Format: Manst DJ, Ganschow PS, Marcus EA, Holden C, Datta S. Intralesional steroid injection: A novel method to treat the symptoms of idiopathic granulomatous mastitis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-10.
Abstract P4-06-30: Adipose PD-L1 modulates checkpoint blockade immunotherapy efficacy in breast cancer
Authors: Wu B , Sun X , Gupta HB , Yuan B , Ge F , Li J , Hu Y , Curiel TJ , Li R
Published: May 2019

Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play important roles in modulating antitumor immune response and are targeted by checkpoint blockade immunotherapy. While PD-L1 expression in both tumor and host cells is associated with antitumor therapeutic efficacy, the exact contribution of PD-L1 in various tissue and cell compartments to antitumor immune response remains to be elucidated. Here we show that PD-L1 expression is markedly elevated in human and mouse mature adipocytes compared to their preadipocyte counterparts. When co-cultured with mouse splenocytes in vitro, adipocytes prevent anti-PD-L1 antibody from activating CD8+T cells. Genetic ablation of adipose PD-L1 obliterates the inhibitory effect of adipocytes on anti-PD-L1 antibody. Conversely, enforced PD-L1 expression in preadipocytes confers the antibody-inhibitory activity. GW9662, a pharmacologic inhibitor of peroxisome proliferator-activated receptor γ (PPARγ) in adipogenesis, selectively reduces PD-L1 expression in mouse adipose tissue. The same PPARγ antagonist also enhances the antitumor efficacy of checkpoint blockade antibodies for treating multiple mammary tumors. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

Citation Format: Wu B, Sun X, Gupta HB, Yuan B, Ge F, Li J, Hu Y, Curiel TJ, Li R. Adipose PD-L1 modulates checkpoint blockade immunotherapy efficacy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-30.
Abstract P4-07-06: Cyclin dependent kinase 7 (CDK7) inhibition with THZ1 induces mitotic failure and increases genomic instability in triple negative breast cancer
Authors: Webb BM , Sahni JM , Keri RA
Published: May 2019

Triple negative breast cancer (TNBC) is highly proliferative and genomically unstable, making these tumors particularly sensitive to anti-proliferative chemotherapies. While efficacious, these drugs induce dose limiting toxicities. Agents that can selectively target proliferation within cancer cells without inducing systemic toxicity should greatly improve patient outcomes from TNBC. In this regard, we have found that TNBC cells are particularly vulnerable to suppression of the transcriptional regulator, LIN9, that controls cell cycle progression. LIN9 mRNA is overexpressed in 66% of TNBCs and is correlated with worse patient outcomes. Moreover, suppression of LIN9 expression induces multi-nucleation, micronucleation, mitotic catastrophe, and cell death and/or senescence. While transcription factors are generally considered “undruggable, LIN9 expression can be pharmacologically suppressed by blocking the activity of cyclin dependent kinase 7 (CDK7) with the selective, covalent CDK7 inhibitor, THZ1. CDK7 inhibitors inactivate RNA polymerase 2 and destabilize the super-enhancer mediated expression of oncogenes. Treatment of three TNBC cell lines (MDA-MB-231, MDA-MB-468, and HCC38) with THZ1 induces G2/M arrest and phenocopies genetic silencing of LIN9. Use of live cell imaging revealed that THZ1 increases the duration of mitosis and also leads to mitosis-associated cell death. Together, these data reveal that CDK7 inhibitors primarily inhibit TNBC growth by causing mitotic dysfunction and potentiating genomic instability by inducing micro- and multi-nucleation. In addition, they suggest that suppressing LIN9 expression by inhibiting CDK7 may lead to a selective approach for targeting proliferation of TNBC and improving patient outcomes from this disease.

Citation Format: Webb BM, Sahni JM, Keri RA. Cyclin dependent kinase 7 (CDK7) inhibition with THZ1 induces mitotic failure and increases genomic instability in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-06.
Abstract P4-07-09: Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032
Authors: Cocco S , Leone A , Buonfanti G , Sisalli MJ , Budillon A , De Laurentiis M
Published: May 2019

Abundant preclinical evidences indicate that stress-induced autophagy in tumor cells is predominantly cytoprotective and that inhibition of autophagy can enhance tumor cell death by diverse anticancer therapies. A major negative regulator of autophagy is the mammalian target of rapamycin (mTOR), activated downstream of PI3KAKT pathway. mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells, while the combination of PI3K-AKT/mTOR and autophagy inhibitors shown synergistic effect on increased apoptosis and reduced autophagy (Takeuchi H. 2005). This project aimed to characterize the role of autophagy in Breast Cancer models exposed to new potent Genentech PI3K/AKT inhibitors GDC0068 (Ipatasertib) and GDC0032 (Taselisib) currently in phase III clinical trials on TNBC and ER+ patients. However, the efficacy of PI3K/AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. In order to investigate the role of autophagy as possible mechanisms of resistance, Ipatasertib and Taselisib have been evaluated in breast cancer cell lines characterized by different receptors profile: TNBC, HER2/c-erb-2 and luminal A cell lines. Our results showed that both drugs are able to induce G1/S cell cycle block and increase of autophagy signaling measured by p62 level and LC3 II/LC3 I ratio and by the percentage of cells exhibiting LC3 positive puncta. In addition, apoptosis increase was also evaluated by measuring positive annexin V staining, by flow cytometry technique, and apoptosis markers, such as PARP and cleaved caspase 3, by immunoblot assay. Furthermore, the supplement of pharmacologic inhibitors of autophagy, such as hydroxichloroquine, were able to reduce cell viability evaluated by both short- and long-term assays in cell lines exposed to Ipatasertib and Taselisib. 3D breast cancer models are ongoing to confirm the synergic effect of PI3K/AKT inhibitors and hydroxychloroquine, in order to provide a new therapeutic combinatorial approach potentially translatable to patients.

Citation Format: Cocco S, Leone A, Buonfanti G, Sisalli MJ, Budillon A, De Laurentiis M. Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-09.
Abstract P4-09-05: Withdrawn
Authors: Veron L , Gelot A , Gusto G , Arveux P , Delaloge S , Boutron-Ruault M-C
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Veron L, Gelot A, Gusto G, Arveux P, Delaloge S, Boutron-Ruault M-C. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-05.
Abstract P4-10-19: Withdrawn
Authors: Gram IT , Braaten T , Lund E , Licaj I
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Gram IT, Braaten T, Lund E, Licaj I. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-19.
Abstract P4-12-05: First implementation of the International Consortium of Health Outcomes Measurement standard for breast cancer at a major German university hospital using a web-based tool to measure patient reported outcomes
Authors: Karsten MM , Speiser D , Hartmann C , Lippold K , Kirchberger V , Blohmer J-U
Published: May 2019

Purpose:

Collecting patient reported outcome (PRO) data in a systematic way enables an objective evaluation of treatments and its related outcomes. By using the disease specific questionnaires developed by the International Consortium of Health Outcome Measurement (ICHOM) this allows for comparison between physicians, hospitals and even different countries.

Methods

In November 2016 we implemented a web-based system to collect PRO data at the breast center at Charité University hospital using the ICHOM data set. All new patients who are seen at the breast center are enrolled and are answering a predefined set of questions using a tablet computer. Once they start their treatment at Charité automated emails are sent to the patient at predefined treatment points. Those emails contain a web-based link through which they can access their questionnaires.

Results

Until now we have enrolled 834 patients and initiated 2470 questionnaires. 9.44% of patients were under 40 years of age, 49.7% between 40 and 60, 39.6% between 60-80 and 1.3% over the age of 80 years. The average return rate of questionnaires is 72% without any additional intervention. When asked about preference regarding paper versus online 7.9% of the patients 50 to 60 years of age would prefer paper, 18% in the 60-70 years of age group and 21.2 % in the age group over 70 years.

Conclusion

Measuring PRO in breast cancer patients in an automated electronic version is possible across all age ranges while simultaneously achieving a high return rate.

Citation Format: Karsten MM, Speiser D, Hartmann C, Lippold K, Kirchberger V, Blohmer J-U. First implementation of the International Consortium of Health Outcomes Measurement standard for breast cancer at a major German university hospital using a web-based tool to measure patient reported outcomes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-12-05.
Abstract P5-03-05: Model of acquired resistance to the tyrphostin NT157 in hormone receptor-positive breast cancer
Authors: Ekyalongo RC , Abdelwahab R , Holtz A , Sabet A , Yee D
Published: May 2019

As previously reported, the small-molecule tyrphostin NT157 binds to the type I insulin-like growth factor-1 receptor (IGF-1R) beta subunit (IGF-IRβ) resulting in degradation of the insulin receptor substrate (IRS) adaptor proteins and inhibits growth of tamoxifen sensitive and resistant ER+ breast cancer cells (Yang, Y. et al. Horm Canc, in press). To investigate effects related to long-term NT157 exposure on IGF signaling, we incubated T47D parental cells in increasing concentrations of NT157 for 20 months. This prolonged exposure resulted in resistant cells (T47D-NTR). Monolayer growth assays showed parental cells inhibited at 0.7 μM of NT157 whereas resistant cells were suppressed by 8 μM of NT157. In parental cells, NT157 caused G0-G1 arrest and an increase in the sub-G1 fraction. However, resistant cells did not show these cell cycle changes after exposure to NT157. Furthermore, the antiproliferative effect of prolonged exposure to 96 hours of NT157 was correlated with decreased activation of Akt/S6k signaling axis and reduction of cyclin D1 expression in T47D parental cells. 48 hours treatment with 5 μM of NT157 resulted in a decrease of IGF-IR and insulin receptor (InR) expression level at 33% and 39% respectively, along with the downregulation of the adaptor proteins IRS-1/2 in only the parental cell line. In resistant cells, the NT157 treatment induced minimal IGF-1R suppression and a 21% increase of IR expression. Additionally, the T47D-NTR cells-maintained IRS protein levels at 10 μM. This absence of IRS protein degradation observed in NT157-resistant cells correlated with the continued expression of estrogen receptor-alpha (ERα), suggesting functional changes within IGF and ERα complex. IGF ligands (IGF-1 or IGF-2) and estradiol (E2) stimulated growth in both cell lines. When NT157 was removed from T47D-NTR cells, they were not re-sensitized to NT157 nor were they affected by IGF dependent growth in the re-introduction of NT157. These findings suggest that resistance to NT157 is mediated by the maintained expression of the IRS adaptor proteins. The continued responsiveness to estradiol and IGF ligands could be due to either a decrease in the drug's half-life or possible changes in NT157 binding to the beta subunit of IGF-IR in resistant cells.

Citation Format: Ekyalongo RC, Abdelwahab R, Holtz A, Sabet A, Yee D. Model of acquired resistance to the tyrphostin NT157 in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-05.
Abstract P5-03-16: KCNN4 confers multiple chemoresistance in breast cancer
Authors: Hu X , Song C-G
Published: May 2019

Multiple chemoresistance is a major unmet clinical obstacle in breast cancer treatment. Here, we uncovered that calcium-activated channel subfamily N member 4 (KCNN4) was an important modulator that limit the cytotoxicity of gemcitabine via a pooled ORF library screen. Importantly, elevating KCNN4 expression enhances the multiple resistance to anti-metabolism chemotherapy drugs, and accelerates cell proliferation. Conversely, silencing or using specific inhibitor, TRAM-34, can counteract its multiple chemoresistance and cell proliferative effects. Mechanically, we found that KCNN4 up-regulated BCL2A1 to suppress cell apoptosis progression via activating RAS-MAPK and PI3K-AKT signaling. In clinical specimens of breast cancer, KCNN4 expression was frequently upregulated and positively correlated with BCL2A1 expression. Moreover, high expression of KCNN4 and BCL2A1 was associated with shorten disease-free survival in studied cohorts. Collectively, our findings showed that KCNN4 was a key modulator in breast tumor progression, implicating that targeting the KCNN4 may serve as a promising therapeutic strategy to overcome multiple chemoresistance in breast cancer.

Citation Format: Hu X, Song C-G. KCNN4 confers multiple chemoresistance in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-16.
Abstract P5-04-09: Not presented
Authors: Mo H , Wang X , Qian Z , Xu B , Ma F
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Mo H, Wang X, Qian Z, Xu B, Ma F. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-09.
Abstract P5-04-24: Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents
Authors: Bathurst L , Liao L , Crozier C , Lyttle N , Marcellus R , Bayani J , Al-awar R , Bartlett J , Spears M
Published: May 2019

Background: Approximately 70% of all breast cancers are estrogen receptor positive (ER+) at diagnosis and are dependent on estrogen signaling for tumour growth and proliferation. Some ER+ breast cancers can be effectively treated with adjuvant endocrine therapies including tamoxifen, but despite favorable improvements in overall survival, resistance to endocrine therapy is common and has been associated with dysregulation of several signaling pathways. These pathways can be targeted with specific inhibitors, many of which are currently under clinical investigation. However currently there is a lack of predictive biomarkers to identify which patients should receive treatment with targeted therapy. The goal of this study was to determine whether alterations in specific signaling pathways can be identified and used to stratify breast cancer cell lines to the most effective experimental treatments.

Methods/Results: Fifteen ER+/HER2- cell lines were characterized using a NanoString PAM50-like assay as well as next generation sequencing and were then stratified according to alterations in three key signaling pathways: CCND/CDK, PI3K/AKT/mTOR and FGFR. High-throughput small-molecule screenings were performed to identify the IC50 values of 24 inhibitors across the strata. Variation in inhibitor sensitivity was observed between cell lines based on molecular alterations. Cell lines with a PIK3CA mutation in combination with a CDK-pathway alteration were more sensitive to CDK inhibitors (50 to 120nM) than cell lines with alterations in the CDK-pathway alone or PIK3CA mutations alone (170nM to >5000nM). In addition, cell lines with the dual alterations demonstrated stronger synergy between CDK and PI3K-pathway inhibitors compared to either alteration alone.

Conclusions: The results suggest that stratification according to molecular alterations in specific signaling pathways may predict sensitivity to targeted inhibitors in a panel of ER+/HER2- luminal breast cancer cell lines. Work is ongoing to identify the optimal synergistic inhibitor combinations for each strata. The ultimate goal is to translate this work into a novel personalized medicine approach, using molecular stratification based on a combination of molecular events in a functional pathway as opposed to single genes.

Citation Format: Bathurst L, Liao L, Crozier C, Lyttle N, Marcellus R, Bayani J, Al-awar R, Bartlett J, Spears M. Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-24.
Abstract P5-05-14: Withdrawn
Authors: Elia AM , Rojas P , Liguori M , Gonzalez P , Caillet I , Martínez Vazquez P , Burruchaga J , Gass H , Lanari C
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Elia AM, Rojas P, Liguori M, Gonzalez P, Caillet I, Martínez Vazquez P, Burruchaga J, Gass H, Lanari C. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-14.
Abstract P5-05-16: Role of estrogen receptor alpha acetylation in estrogen-dependent gene regulation in breast cancers
Authors: Vasquez YM , Setlem R , Murakami S , Kraus WL
Published: May 2019

Estrogens, such as 17β-estradiol (E2), act through estrogen receptor alpha (ERα), a ligand-regulated transcription factor that binds across the genome to promote enhancer formation and regulate gene expression. ERα is expressed in approximately 70% of breast cancers, where it regulates the transcription of genes involved in mitogenic and inflammatory pathways. We are exploring the the acetylation of ERα on lysines 266 and 268, a modification that enhances the DNA binding and transcriptional activities of ERα. ERα acetylation is catalyzed by the lysine acetyltransferases p300 and CBP in an E2- and steroid receptor coregulator (SRC)-dependent manner. Acetylation-dependent activation of ERα has potential implications in breast cancers associated with enhanced coregulator interactions, such as SRC-3/Amplified in Breast (AIB1) gene amplifications and gain-of-function ERα mutations in endocrine resistant metastatic tumors, such as Y537S and D538G. Increased association of ERα with SRCs and p300/CBP leading to enhanced ERα acetylation may promote gain-of-function ERα activity. Our hypothesis is that acetylation of ERα alters its function by increasing E2-responsive gene transcription and signaling in breast cancers. Our current efforts are focused on investigating the role of ERα acetylation on chromatin binding and accessibility, enhancer activity, and target gene transcription. We are using the ER-positive MCF-7 breast cancer cell line with a knockdown/re-expression strategy with biochemical mimics of acetylated (K266/268Q) or unacetylated (K266/268R) ERα. Genomic ERα binding profiles using chromatin immunoprecipitation-sequencing (ChIP-seq) has defined overlapping, but unique, sets of transcriptional targets and recruitment kinetics for the ERα mutants. Current efforts are focused on defining global transcriptional responses associated with the unique binding activities using precision run-on sequencing (PRO-seq). Ultimately, our goal is to define how acetylation affects the binding of ERα to chromatin and its effect on the transcriptional activity of E2-target genes in breast cancers in the context of gain-of-function ERα mutations and coregulator amplifications. Supported in part by a postdoctoral fellowship from the Lalor Foundation to YMV, and grants from the NIDDK, NICHD, and CPRIT to WLK, as well as support from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment.

Citation Format: Vasquez YM, Setlem R, Murakami S, Kraus WL. Role of estrogen receptor alpha acetylation in estrogen-dependent gene regulation in breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-16.
Abstract P5-07-04: Not presented
Authors: Chatterjee S , Basak P , Tan S , Lefort S , Pellacani D , Safneck J , Buchel E , Aparicio S , Eaves CJ , Raouf A
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Chatterjee S, Basak P, Tan S, Lefort S, Pellacani D, Safneck J, Buchel E, Aparicio S, Eaves CJ, Raouf A. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-04.
Abstract P5-07-12: Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s
Authors: He Y , Tang J
Published: May 2019

Background

Metastatic breast cancer remains incurable and underlying mechanisms are poorly understood. Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports breast cancer metastasis. Circular RNAs are new class of endogenous noncoding RNAs. Unlike linear RNAs terminated with 5'caps and 3'tails, they uniquely have a covalently closed loop structure, making them stable and ideal candidate biomarkers. Here, we identified a circular RNA and explored for the first time how it played a dual role in epithelial to mesenchymal transition (EMT) and macrophage recruitment.

Methods

We first analyzed TCGA database about whether mesenchymal tumors could be more likely to recruit TAMs. ELISA assay was performed for determining expression level of chemokines (CSF-1, CCL2, CCL5, C5a, VEGFA, IL-34) after cell line MCF-7 finishing EMT. Next, we predicted microRNAs which could regulate CSF-1 expression and inhibit EMT using Targetscan database. Circular RNA was identified via comparing expression levels between mesenchymal-like and epithelial-like cells using circRNA microarrays. The specific mechanisms were explored via series of molecular biology assays in vitro and in vivo.

Results

Correlation analysis of relationship between EMT score and expression of all classical chemokines that could recruit macrophage revealed a positive association (r2>0.3, P<0.05) among 1079 breast cancer cases. Increased expression level of CSF-1 was found the most significant after EMT. miR-200b and miR-200c that inhibiting breast cancer EMT were confirmed targeting 3'UTR of CSF-1 mRNA and decreasing migration of TAMs. Circular RNA NCAPG (circNCAPG) was found highly expressed in mesenchymal-like cells and could promote breast cancer metastasis in vitro and in vivo. Poor clinical outcome was found in circNCAPG overexpression group among 141 breast cancer cases. CircNCAPG was proven to be located in cytoplasm and found could act as the sponge of miR-200b and miR-200c. Moreover, expression level of CSF-1 and ZEB-1 (also targeted by miR-200s and regulating key process of EMT) was found decreasing significantly after knocking down circNCAPG both in vitro and in vivo, leading to breast cancer metastasis inhibition.

Conclusion

Mesenchymal tumors have the ability to recruit more TAMs, therefore further promoting breast cancer metastasis. A new molecule: circNCAPG participates in this process via acting as the sponge of miR-200s and regulates CSF-1 and ZEB-1 expression, which warrants further study in clinical settings.

Citation Format: He Y, Tang J. Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-12.
Abstract P5-08-04: Defining chromatin accessibility profiles of partial and reversible EMT
Authors: Johnson KS , Hussein S , Lin Y , Taube JH
Published: May 2019

The epithelial-to-mesenchymal transition (EMT) reversible cellular reprogramming event, used repeatedly throughout development, is hypothesized to be involved in the cell migration and consequently metastasis that ultimately contributes to most breast cancer-related fatalities. In this process, cuboidal epithelial cells, marked by the presence of tight junction proteins and cell-cell adhesions, lose their apicobasal polarity and acquire a spindle-like morphology and migratory traits. EMT was originally regarded to have only two states, with cells exhibiting either epithelial or mesenchymal phenotypes; however, recently, researchers have demonstrated the existence of a dual epithelial/mesenchymal state, termed hybrid- or partial-EMT. Due to its inherent plasticity, it is believed that EMT and its reversal mesenchymal-to-epithelial transition (MET) is, at least, partly regulated by epigenetic means such as alterations in chromatin structure. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a novel technique that employs the use of a mutant Tn5 transposase to cleave nucleosome-free DNA regions in a non-biased manner. In this investigation, we induced MCF10A mammary epithelial cells to undergo a short-term (<4 days) or long-term (>4 days) EMT. Addition and withdrawal of exogenous TGFβ1 produced partial- or full-EMT and MET conditions which were interrogated by ATAC- and RNA-seq. Hierarchical clustering of ATAC cleavage peaks revealed that pre-EMT and short- and long-term MET conditions demonstrate similar chromatin accessibility profiles with cleavage sites enriched for specific binding motifs. Notably, transcription factors typically not associated with EMT displayed dynamic enrichment in the accessible chromatin at various timepoints in our assay. Correlation with RNA-seq data reveals highly dynamic changes in gene expression suggesting dynamic and reversible use of regulatory programs. Importantly, partial-EMT cells were characterized by unique accessibility patterns, motif enrichment, and gene expression supporting the conclusion that this is not merely an intermediate but a unique state.

Citation Format: Johnson KS, Hussein S, Lin Y, Taube JH. Defining chromatin accessibility profiles of partial and reversible EMT [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-04.
Abstract P5-08-05: The interplay between stromal density, epithelial mesenchymal transition and chemoresistance in breast cancer
Authors: Agarwal V , Spalding LJ , Blick T , Dobrovic A , Thompson EW , Redfern A
Published: May 2019

Epithelial Mesenchymal Transition (EMT) refers to the transition of cells from a more differentiated epithelial phenotype to a less differentiated mesenchymal phenotype, a process that may be triggered by a range of therapeutic interventions including cytotoxic treatment, and which we have previously linked to poor breast cancer (BrCa) outcome after neoadjuvant chemotherapy (NAC)1. Mammographic breast density (MBD)represents the white radiographic appearance of epithelial and stromal breast tissue on a mammogram. High MBD in patients being treated for BrCa also associates with chemoresistance, correlating with lower pathological complete response rates (pCR)2. Linking these two stimuli, EMT can also be induced by artificial high-density stroma, where it also leads to chemoresistance in vitro3.

Here we set out to validate the link between poor outcome after NAC and EMT in a larger validatory patient cohort, and to ascertain the molecular drivers through which EMT is triggered in this setting. Further we look to confirm the association of high MBD with poor chemoresponse in the same cohort, and to assess whether this chemoresistance is mediated through EMT with the same drivers.

In a pilot cohort of 50 NAC-treated locally advanced BrCas with a pCR rate of 20%, pre-NAC biopsies and post-NAC surgical specimens were analysed for expression changes in a panel of EMT-related markers across treatment using 230 Nanostring assays. This included the EMT-driving transcription factors TWIST 1 and 2, SNAIL 1, 2 and 3 and ZEB 1 and 2, which were correlated with risk of relapse. Snail-3 showed significantly greater induction in relapsers compared to non-relapsers (OR=1.8, p=0.04) with a borderline significantly greater induction of TWIST-1 (OR=2.4, p=0.08) in relapsers in addition.

In a subsequent 240-patient validation cohort with a pCR rate of 18%, contralateral cranio-caudal view mammograms from the time of diagnosis have been collated and digitized with MBD assessment employing Cumulus software ongoing. Percent breast density will be assessed both as a continuous variable and by quartiles. Immunohistochemistry on pre- and post-operative tissue sections with pan-cytokeratin-vimentin co-staining to identify EMT and staining for SNAIL-3 and TWIST-1 is also in progress.

Associations between MBD, EMT before and after chemotherapy, pCR and relapse-free survival will be presented. The role of Snail-3 and TWIST-1 in the interplay between MBD, EMT and outcome is being explored and will be reported.

Citation Format: Agarwal V, Spalding LJ, Blick T, Dobrovic A, Thompson EW, Redfern A. The interplay between stromal density, epithelial mesenchymal transition and chemoresistance in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-05.
Abstract P5-09-14: Prevalence and type of BRCA mutations in young breast cancer patients undergoing genetic cancer risk assessment in two developing countries: Analysis of two cohorts from Romania and Mexico
Authors: Campos-Gomez S , Antone N , Pacheco-Cuéllar G , Pop L , Campos  Gomez K , Stoian A , Eniu R , Valdes-Andrade J , Dronca E , Matei R , Ligtenberg M , Ouchene H , Onisim A , Rotaru O , Eniu AE
Published: May 2019

Background: a previous study found significant clinicopathological differences between young Breast Cancer BrCA patients (pts) from Romania (Ro) and from Mexico (Mx). Here, we provide a molecular and clinical description of pts carrying BRCA mutations of both cohorts.

Methods: in this retrospective study, we analyzed 2 cohorts of BRCA1/2 mutations carriers tested in COEI from Mx between 2014-2017 and IOCN from Ro between 2015 to 2016. Ro pts were selected according to NCCN criteria, while Mx pts were selected based on risk evaluation models. NGS analysis and MLPA for BRCA1&2 were performed in all pts. We compared demographic, clinicopathological and molecular data.

Results: 65 pts, 21 (32.7%) from Mx and 44(67.7%) from Ro carried a BRCA mutation. 66.7% of Mx pts and 65.9% of Ro pts carried a BRCA1 mutation. We found clinical similarities: Mean age was 44.5y for Mx and 40.59y for Ro pts. IDC was the most frequent type of BrCa in both series (90.5 vs 90.9%). TNBC was seen in 13 Mx vs 27 Ro pts (61.9% vs 61.4%), HR positive was seen in 7 (33.3%) and 12 (27.3%) cases. Grading 3 was more frequently seen in Ro, while grading 2 was mainly noted in MX pts(p=<0.020). BRCA1/2 pathogenic mutations were different between the 2 cohorts and no BRCA 1/2 identical mutation was identified. 15 different mutations in 21 Mx pts, and 16 different mutations in 44 Ro pts were found. Mutations were different between 2 cohorts. Notably for the Ro cohort, 4 founder mutations (c.181T>G, c.3607C>T, c.5266dupC in BRCA1,and c.9928A>G[GPC1] in BRCA2) were found in 31/44 pts, while the Mx cohort, c.5123C>A and del 9-12del ex in BRCA1 were found in 6/21 mutations. Three Large rearrangements (LR) were exclusively seen in the Mx pts (5/21).

Conclusions Both cohorts didn't share any mutation, but the clinical features are similar. BRCA1 del 9-12del is a Mexican founder mutation, we found it in 14% of Mx pts, LR have been described more frequently in Latin American Populations, we found it in 30% of the MX cohort, while for Ro cohort four recurrent mutations qualify as founder mutations.

Citation Format: Campos-Gomez S, Antone N, Pacheco-Cuéllar G, Pop L, Campos Gomez K, Stoian A, Eniu R, Valdes-Andrade J, Dronca E, Matei R, Ligtenberg M, Ouchene H, Onisim A, Rotaru O, Eniu AE. Prevalence and type of BRCA mutations in young breast cancer patients undergoing genetic cancer risk assessment in two developing countries: Analysis of two cohorts from Romania and Mexico [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-14.
Abstract P5-09-21: Not presented
Authors: Servais L , Gardner A , Gomes M , Zimmer AD , Silvestrini A , Siqueira de Abreu e Lima R
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Servais L, Gardner A, Gomes M, Zimmer AD, Silvestrini A, Siqueira de Abreu e Lima R. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-21.
Abstract P5-10-04: Exome sequencing in high breast and ovarian cancer incidence families which lack detectable mutations in established cancer susceptibility genes
Authors: Kenny PA , Girtman MA , Deviley JA , Meier DR , Vos CR , Richmond CS , Lofgren KA
Published: May 2019

At our center, a standard 25 gene panel has proved useful for the identification of pathogenic germline mutations in many families with a high penetrance of breast and ovarian cancer, yet there remain several families with very high cancer incidence but from whom these assays have not identified pathogenic alleles. To attempt to define the genetic mechanism of susceptibility in such cases, are conducting germline whole exome sequencing in affected individuals. Here we describe the identification of strong candidate susceptibility variants in two such families. Both variants cause loss-of-function of DNA repair genes not previously implicated in breast cancer, but which share properties with genes with known roles in maintenance of genome integrity. In one individual, with a personal history of ovarian cancer and two independent breast tumors, we identified a novel point mutation in POLD2 which introduces a mutation at a residue which is biochemically conserved in all animal species thus far sequenced. In the second individual, a frameshift mutation was detected in ERCC4. In both cases, the variants found have not been observed in large exome datasets (e.g. ExAC) or reported in ClinVar. Our study highlights the potential utility of whole exome sequencing as a discovery tool in those families with high cancer incidence yet which lack mutations in known hereditary cancer predisposition genes.

Citation Format: Kenny PA, Girtman MA, Deviley JA, Meier DR, Vos CR, Richmond CS, Lofgren KA. Exome sequencing in high breast and ovarian cancer incidence families which lack detectable mutations in established cancer susceptibility genes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-04.
Abstract P5-11-08: Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine
Authors: Xu J , Sun T , Wang X
Published: May 2019

Background: CDK4/6 inhibition combined with endocrine therapy is now a standard of care for advanced estrogen receptor (ER) positive breast cancer. Predictive genetic landscape and mechanisms of resistance to CDK4/6 inhibitors have not been described clearly because of limited evidence from clinical samples. We investigated the genetic landscape and mechanisms of resistance to CDK4/6 inhibitors (palbociclib or abemaciclib).

Methods: Using driver mutation targeted sequencing, we conducted longitudinal ctDNA analysis in 39 pairs of baseline of primary tumor and end of treatment or monitoring plasma samples. DNA were extracted and the genomic profiles were analyzed based on NGS.

Results: In our cohort, the most frequence mutations were PIK3CA (38.5%), TP53(17.9%), CCND1, ZNF703, FGFR1, MAP2K4, RB1, ARID1A, ATRX, DNMT3A. In five paitents harboring RB1 mutations prior to CDK4/6 inhibitor, only one case occured progressing early with 4mos of PFS, and the others were 5.5+, 6.5+, 13.5+, 21+months, it represented different from pre-clinical results that RB1 mutation was associated with resistance to CDK4/6 inhibitor. Interesting, patients with PIK3CA/PTEN/AKT1 mutations (n=15) were likely sensitivity to CDK4/6 inhibitor than those (n=11) with wild type (median PFS: 17 mos vs. 9.5mos, P=0.046). In another cohort of everolimus, new driver mutations emerged in both FGFR1 and ERBB3 at end of everolimus and significantly disappeared in AKT1 mutation. Three patients used palbociclib after progress disease of everolimus, the prognosis were poor with PFS of 1, 6, 9 mos. Evolution of driver gene mutations was uncommon in patients progressing on CDK4/6 inhibitors treatment, but common in patients progressing on everolimus treatment.

Conclusions: De novo PIK3CA/PTEN/AKT1 mutations were likely better prognosis biomarkers with the treatment of CDK4/6 inhibitor. RB1 mutation are common and may not contribute to CDK4/6 inhibitor resistance differ from PALOMA3 ctDNA analysis. Our small sample finding indicate it may be a bad stragegy for CDK4/6 inhibitor after progress disease with mTOR inhibitor everolimus.

Citation Format: Xu J, Sun T, Wang X. Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-08.
Abstract P5-13-02: Not presented
Authors: Rositch AF , Ginsburg OM , Huang L , Chao CA , Visvanathan K , Masalu N
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Rositch AF, Ginsburg OM, Huang L, Chao CA, Visvanathan K, Masalu N. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-02.