bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-18-01: Treatment benefit of ribociclib + letrozole in patients with de novo disease and visceral metastases from the MONALEESA-2 study
Authors: O'Shaughnessy JA , Arteaga CL , Hart LL , Lindquist DL , Beck JT , Purkayastha DD , Caria N , Hortobagyi GN 
Published: May 2019

Abstract
Background: Ribociclib (ribo) + letrozole (LET) demonstrated efficacy and safety in first-line treatment of patients (pts) with hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC). Most endocrine therapy (ET)–naive pts with de novo ABC respond to ET, but first-line monotherapy with ET or fulvestrant elicited only moderate efficacy in the FALCON study of pts with visceral metastases (mets). Visceral mets are associated with poor prognosis and may warrant novel treatment options in addition to ET. Here, we present clinical outcomes of treatment with ribo in pts with de novo ABC and visceral mets.
Methods: In the MONALEESA-2 study, postmenopausal women with HR+, HER2− ABC (N=668) were randomized (1:1) to receive either ribo 600 mg/d or placebo (3 wk on/1 wk off) + LET 2.5 mg/d (continuous). The primary endpoint was median progression-free survival (mPFS).
Results: All pts in this analysis (n=227) had de novo ABC; 108 pts had visceral mets (ribo, n=53; placebo, n=55). Baseline characteristics were similar between the ribo and placebo groups. The median follow-up time was 26.4 months. In pts with visceral mets, mPFS was significantly higher in the ribo group (30.3 months) than in the placebo group (14.1 months; hazard ratio, 0.52; 95% CI, 0.295–0.905; P=0.019). Rates of PFS in these pts in the ribo vs placebo group, respectively, were 76% vs 60% at 12 months and 60% vs 36% at 24 months. Among the pts with visceral mets, clinical benefit rate (CBR) was 79% vs 71% in the ribo vs placebo group, and overall response rate (ORR) in pts with measurable disease at baseline was 55% vs 46%, respectively. In pts without visceral mets (ribo, n=61; placebo, n=58), PFS rates in the ribo vs placebo group, respectively, were 87% vs 72% at 12 months and 66% vs 51% at 24 months. Safety results were consistent with the overall population, and responses were durable with ribo + LET irrespective of whether the pts had visceral or nonvisceral mets.
Conclusions: Clinical outcomes from this analysis of the MONALEESA-2 study are consistent with those of the overall population, and ribo + LET prolonged the mPFS and improved ORR and CBR in pts with de novo ABC with visceral mets vs placebo + LET.
Citation Format: O'Shaughnessy JA, Arteaga CL, Hart LL, Lindquist DL, Beck JT, Purkayastha DD, Caria N, Hortobagyi GN. Treatment benefit of ribociclib + letrozole in patients with de novo disease and visceral metastases from the MONALEESA-2 study [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 P6-18-01.
Abstract P6-18-13: Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor in triple negative breast cancer
Authors: Shariati M , Paez-Arango N , Bristow CA , Evans KW , Peoples MD , Carugo A , Heffernan TP , Meric-Bernstam F 
Published: May 2019

Abstract
Triple-negative breast cancer (TNBC) is among the most aggressive subtypes, accounts for 10-15% of all breast cancer cases and is characterized by a lack of hormone receptors with a low overall survival rate. Due to the heterogeneity nature of this disease, the absence of validated molecular targets makes it unresponsive to conventional therapies. PI3K/Akt/mTOR pathway is aberrantly activated in TNBC, but single agent therapy is commonly subject to resistance. The goal of this study is to identify the genes that can be targeted to enhance the efficacy of mTOR inhibitor TAK228, an agent that is being investigated as a treatment for advanced solid tumors, in TNBC with PI3K pathway activation. We utilized an in vivo pooled barcoded shRNA library screening to determine the genes that have the potential to be used as TAK228 synthetic lethal partners. Using deep sequencing analysis of the shRNA profiles, we identified several genes whose loss of function conferred synthetic lethality in the presence of TAK228. We found that targeting the candidate genes (WEE1, BMX and MAPK15) with their inhibitors (AZD1775, Ibrutinib and Sunitinib) did not significantly affect the viability, however combination treatment of these agents with TAK228 induced a robust growth inhibition and demonstrated a significant synergy in MDA-MB-468 cell lines. Investigating the activation of relevant survival signaling pathways will further elucidate the mechanism of synthetic lethal interaction. These observations provide a promising rational strategy for the treatment of TNBC with PI3K pathway aberration.
Citation Format: Shariati M, Paez-Arango N, Bristow CA, Evans KW, Peoples MD, Carugo A, Heffernan TP, Meric-Bernstam F. Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor 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 P6-18-13.
Abstract P6-18-33: GI toxicities in metastatic breast cancer: A comprehensive literature review
Authors: Disher T , Siddiqui M , Mitra D , Cameron C , Zhan L , Iyer S 
Published: May 2019

Abstract
Background
Treatments for advanced or metastatic breast cancer (aBC/mBC) are associated with gastrointestinal (GI) toxicities. The objective of this study was to assess the association between GI toxicities in mBC/aBC and health-related quality of life (HRQoL) and economic burden.
Methods
We conducted a comprehensive literature search of the Cochrane Central Register of Controlled Trials (2017), NHS Economic Evaluation Database (2016), Embase (1988 – 2017 week 34), and Ovid MEDLINE (1946 to August 2017). Eligible studies evaluated an intervention/comparator treatment in adult patients (age ≥18 years) with aBC/mBC and reported a direct connection between GI toxicities (ie, diarrhea, constipation, nausea, vomiting) and HRQoL and economic evidence. All studies published from January 2000 to August 2017 were assessed for eligibility. Editorials, case reports, conference abstracts, and studies of early, locally advanced, or inflammatory BC were excluded. Abstract and title screening, and full-text screening were conducted by single reviewers. Data were extracted by a single reviewer and verified by a second. Results were synthesized narratively.
Results
Database searches identified 3,428 articles; an additional 16 articles were identified through other sources. Ninety-four studies underwent full-text review, of which 27 reported a direct connection between GI toxicities and HRQoL (n = 11) and economic burden (n = 19). Some studies reported both HRQoL and economic data.
Patients identified treatment-related adverse events (AEs), such as GI events, as an important aspect of treatment that can affect therapy choice, discontinuation, and switching. Generally, patients with mBC had lower HRQoL than other BC groups, and increasing toxicity was associated with a greater degree of HRQoL impairment. When patients were asked to rank which AEs they most wanted to avoid, only pain ranked higher than nausea and vomiting. In a willingness to pay study, women with mBC were willing to pay $3,894 (2014 USD) per year to avoid severe diarrhea and $3,211 to avoid severe nausea.
Gastrointestinal events were among the costliest class of AEs, with mean costs as high as $4,809 (2016 USD) per episode; costs increased by 24% if events were persistent or recurrent.
Conclusions
Gastrointestinal toxicities are common in patients with aBC/mBC and have significant consequences for HRQoL and system-level economic outcomes. Frequency and implications of GI effects of treatment regimens should be considered carefully during patient counseling,, prescribing and coverage decisions in metastatic breast cancer.
Citation Format: Disher T, Siddiqui M, Mitra D, Cameron C, Zhan L, Iyer S. GI toxicities in metastatic breast cancer: A comprehensive literature review [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 P6-18-33.
Abstract P6-19-06: Breast conservation surgery in male breast cancer: A systematic literature review
Authors: Fisher CS , de la Cruz L , Joshi S , Mah T-J , Blankenship S , Thiruchelvam P 
Published: May 2019

Abstract
BACKGROUND
Male breast cancer (BC) incidence is low and management is extrapolated from female BC. Breast conservation surgery (BCS) is commonly used for female BC, however, mastectomy remains the most frequently used surgical procedure for male breast cancer. We performed a literature review to assess the use of BCS in male BC as well as outcomes following BCS.
METHODS
A systematic literature review identified peer-reviewed articles in PubMed evaluating male BC and surgery. Abstracts were screened to identify studies that measured overall survival (OS), disease-free survival (DFS), or local recurrence (LR) in patients undergoing BCS. For all studies, we extracted the total number of patients and number of BCS cases. Of patients undergoing BCS, we further extracted mean age, mean follow-up time, clinical stage, type of axillary surgery [sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND)], radiation therapy, hormonal therapy, and chemotherapy. Weighted averages, based on number of patients in each study, were performed for LR, DFS and 5-year OS. The time period for LR and DFS was the duration of follow-up time for each study.
RESULTS
The literature search yielded 4341 articles. Twelve studies published from 1998 to 2016 met the inclusion criteria and were selected for the systematic literature review. Among the 12,616 male breast surgery cases included, 1,633 (12.9%) underwent BCS. Only patients who underwent BCS were included in our analysis. The mean follow-up time was 54.4 months and mean age was 62.4 with stage II as the most common presentation. Two studies reported that 50-71.4% of patients underwent SLNB and 4 studies reported ALND in 14.3-100%. Seven studies reported that adjuvant radiation therapy was administered in 12.0-100% of 474 total patients undergoing BCS. Four studies reported use of hormonal therapy in 73.8-100% of patients. Four studies reported use of chemotherapy in 25-66.7% of patients. Seven studies reported LR among 122 patients, with a weighted average 11.8%. Four studies reported on 5-year OS in 1511 patients, with a weighted average of 85.8%.
CONCLUSION
While less commonly used than mastectomy, BCS can be considered a safe alternative in the surgical treatment of male BC. We have demonstrated that the use of adjuvant radiation following BCS is variable in this patient group. Future research should focus on better standardization of local therapy for male BC and improved reporting of outcomes.
Citation Format: Fisher CS, de la Cruz L, Joshi S, Mah T-J, Blankenship S, Thiruchelvam P. Breast conservation surgery in male breast cancer: A systematic literature review [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 P6-19-06.
Abstract P6-20-05: Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation
Authors: Na B , Yu X , Wither T , Gilleran J , Yao M , Foo TK , Chen C , Moore D , Xia B , Lin Y , Kimball D , Ganesan S , Carpizo D 
Published: May 2019

Abstract
Triple negative breast cancer (TNBC) is an aggressive subset for which novel therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc Metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate a class of zinc deficient mutant TP53 alleles by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using genetically engineered murine mammary tumor models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival in mice bearing tumors harboring the zinc deficient Trp53R172H allele but not the Trp53 null allele. We synthesized a novel formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy over ZMC1. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for tumors expressing the p53R172H mutant. In conclusion, we have validated preclinically a novel therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53.
Citation Format: Na B, Yu X, Wither T, Gilleran J, Yao M, Foo TK, Chen C, Moore D, Xia B, Lin Y, Kimball D, Ganesan S, Carpizo D. Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation [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 P6-20-05.
Abstract P6-20-15: Characterization of a novel prognostic and targetable modulator of the Wnt/β-catenin signaling pathway in breast cancers
Authors: Bunnag N , Yuan Y , Cai W , Suresh J , Young Bok L , Deog Joong K , Tolwinski N , Kumar AP 
Published: May 2019

Abstract
Mortality in metastatic triple negative breast cancer (TNBC) remains high due to a lack of targeted therapy options. Consequently, there is a pressing need to identify prognostic markers and therapeutic targets for TNBC. Our group identified the DEAD-box RNA helicase DP103 as a novel prognostic biomarker and metastasis-driving oncogene enriched in TNBC. Aberrant Wnt/β-catenin signaling has been implicated for driving growth and metastasis of many cancers, like TNBC. Our studies found that the depletion of DP103 in metastatic TNBC cells resulted in decreased Wnt activity and expression of downstream Wnt target genes such as Axin2 and c-Myc. In addition, stimulation of the Wnt pathway via GSK3β inhibition or Wnt-3a recombinant protein significantly increased the transcriptional expression of DP103, indicating a possible positive feedback loop. To validate this new role for DP103 in regulating the Wnt/β-catenin signaling pathway in vivo, we developed a novel Drosophila stem cell and tumor model by generating a genetic mosaic of oncogenic Ras and β-catenin in Drosophila. The co-expression of these oncogenes caused benign tumor formation in Drosophila larval tissue that were visualized and used to identify key genetic modifiers necessary for growth and invasion into neighboring tissues. RX-5902, a novel Wnt/β-catenin modulator preventing the nuclear translocation of β-catenin via phosphorylated p68 decreased the transcriptional expression of DP103 and inhibited tumor formation as observed in our Drosophila model. Interestingly, overexpression of DP103 abrogated the effects of RX-5902, suggesting a requirement for RX-5902-mediated downregulation of DP103 to bring about anti-tumorigenic effects. Collectively, our data suggests a novel regulatory role for DP103 in the Wnt/β-catenin signaling pathway that is targetable by drugs like RX-5902.
Citation Format: Bunnag N, Yuan Y, Cai W, Suresh J, Young Bok L, Deog Joong K, Tolwinski N, Kumar AP. Characterization of a novel prognostic and targetable modulator of the Wnt/β-catenin signaling pathway 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 P6-20-15.
Abstract P6-20-17: Targeting SHP2 for the treatment of HER2-positive breast cancer
Authors: Agazie Y , Hartman Z 
Published: May 2019

Abstract
Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth factor receptor 2 (HER2). As a result, several antibody-based and small molecule-based anti-HER2 therapies have been developed. These drugs have benefited BC patients by improving overall survival and quality of life. However, development of resistance and disease recurrence have been the major clinical challenges. One way to overcome these clinical problems is to develop alternative therapeutic strategies. Multiple lines of evidence show that targeting the Src homology phosphotyrosyl phosphatase 2 (SHP2) in HER2-positive BC may prove beneficial both in treatment-naïve and anti-HER2 therapy-resistant forms of the disease. For instance, silencing SHP2 expression in HER2-positive breast cancer cells or conditional knockout in ErbB2 transgenic mice blocks HER2 overexpression and associated signaling, leading to loss of cell transformation and tumorigenesis. To test the clinical translational significance of SHP2 targeting, we have invented a specific small molecule SHP2 inhibitor named WGMDY (US 9,932,288) that has shown promising anti-cancer effects. The results obtained so far show that inhibition of SHP2 with WGMDY blocks HER2 expression, suppresses cell proliferation and anchorage independent growth, and induces regression of preformed xenograft tumors. These findings suggest that SHP2 might be an excellent drug target for HER2-positive BC and WGMDY has a promising potential to serve as a lead compound for developing anti-SHP2 drugs.
Citation Format: Agazie Y, Hartman Z. Targeting SHP2 for the treatment of HER2-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 P6-20-17.
Abstract PD2-04: Baseline circulating ESR1 mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced hormone receptor positive breast cancer
Authors: Turner N , Swift C , Kilburn L , Garcia-Murillas I , Johnston S , Budzar A , Robertson J , Gradishar W , Piccart M , Schiavon G , Chia S 
Published: May 2019

Abstract
Background. ESR1 mutations are acquired frequently in hormone receptor positive breast cancer after treatment with aromatase inhibitors (AI) in the metastatic setting. In prior analysis of the SoFEA phase III randomised trial, we demonstrated the detection of ESR1 mutations in circulating tumor DNA (ctDNA) predicted for greater benefit of fulvestrant compared to exemestane (Fribbens et al JCO 2016).
Methods. The phase III EFECT study randomised 693 patients with ER+ metastatic breast cancer who had progressed on a prior non-steroidal AI, between fulvestrant loading dose and then 250mg q28 days and exemestane (Chia S, et al. J Clin Oncol 2008). Baseline serum samples were available from 227 patients in EFECT, and were analysed for the 8 most common ESR1 mutations by multiplex digital PCR. The association between baseline ESR1 status and time to progression (TTP) was analysed using Kaplan-Meier methods.
Results. ESR1 mutations were successfully analysed in 98% (222/227) of patients with baseline serum samples, with ESR1 mutations detected in 23.4% (52/222) samples. Overall, detection of ESR1 mutations at baseline was associated with shorter TTP (hazard ratio [HR] 2.03, 95% CI 1.26-3.29, p=0.004). In patients with ESR1 mutation detected, TTP was 2.0 months (95%CI, 1.7-2.4) on exemestane and 3.5 months (95%CI, 1.9-5.0) on fulvestrant (HR 0.67, 95%CI 0.37-1.19, p=0.17). In patients without ESR1 mutations detected, TTP was 4.5 months (95%CI, 3.7-5.6) on exemestane and 3.7 months (95%CI, 3.3-5.2) on fulvestrant (HR 1.05, 95%CI 0.75-1.45, p=0.78). A meta-analysis of SoFEA and EFECT will be presented at the conference.
Conclusions. Historical serum samples may be used for ctDNA analysis, illustrating the potential for future research of sample archives. Patients with ESR1 mutation detected in ctDNA have poor outcome when treated with exemestane, replicating prior results from SoFEA and demonstrating clinical utility for ESR1 mutation ctDNA analysis.
Citation Format: Turner N, Swift C, Kilburn L, Garcia-Murillas I, Johnston S, Budzar A, Robertson J, Gradishar W, Piccart M, Schiavon G, Chia S. Baseline circulating ESR1 mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced 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 PD2-04.
Abstract PD7-01: Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma
Authors: Haley K , Walsh L , Moran B , Das S , Tarrant F , Caldas C , Bernards R , Gallagher W , O'Connor D , Ni Chonghaile T 
Published: May 2019

Abstract
Invasive lobular carcinoma (ILC) is a subtype of breast cancer comprising 10% of breast tumours. ILC is characterised by a loss of E-cadherin, and is generally estrogen receptor (ER) positive. The majority of ILC breast cancers are treated with endocrine therapy, although approximately one in three women are de novo resistant to therapy. To identify novel therapeutic targets for the treatment of ILC, we carried out RNA sequencing on 61 primary ILC samples. We found that high expression of the epigenetic reader, bromodomain protein 3 (BRD3) was associated with poor recurrence free survival. We also validated this finding in a separate cohort of 99 ILC patient samples using the METABRIC cohort. Next, we assessed ILC cell lines for sensitivity to JQ1, an inhibitor of BET family proteins. We found that JQ1 inhibited cell growth in all the cell lines tested. Interesting, two of the ILC cell lines were sensitive to JQ1-induced apoptosis, whereas two of the cell lines were inherently resistant to JQ1-induced apoptosis. Using dynamic BH3 profiling we showed that the JQ1 resistant cell lines were dependent on anti-apoptotic protein BCL-XL following JQ1 treatment. Interestingly, we show both in 2D and 3D cultures that JQ1 is synergistic when combined with the BH3 mimetic, ABT-263. Highlighting that combination treatment with JQ1 and ABT-263 may be a novel potential therapeutic option for ILC.
To unveil the mechanism underlying resistance to JQ1-induced apoptosis, we performed paired-end RNA sequencing and compared differentially expressed genes in JQ1 sensitive and JQ1 resistant ILC cell lines. DAVID gene ontology analysis identified 6 pathways differentially upregulated in the JQ1 resistant ILC cell line including MAPK, Wnt, and insulin resistance signaling. Interestingly, we found that ILC cell lines, which were resistant to BET inhibition with JQ1, demonstrated high levels of FGFR1-4 both at the mRNA level and the protein level. Combination treatment with JQ1 and the FGFR1 inhibitor PD173074 or following knockdown of FGFR with siRNA, resulted in increased cell death in JQ1 resistant cells. Currently, we are assessing how FGFR signaling enables survival of ILC cells following JQ1 treatment and determining the exact function of BRD3 in ILC. In conclusion, we have identified a novel therapeutic target, BRD3, which may be inhibited using JQ1 in combination with BH3 mimetic ABT-263 or FGFR1 inhibitor for a more effective treatment strategy for ILC.
Citation Format: Haley K, Walsh L, Moran B, Das S, Tarrant F, Caldas C, Bernards R, Gallagher W, O'Connor D, Ni Chonghaile T. Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma [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 PD7-01.