bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-02-01: NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing breast cancer
Authors: Lécuyer L , Victor Bala A , Deschasaux M , Bouchemal N , Nawfal Triba M , Vasson M-P , Rossary A , Demidem A , Galan P , Hercberg S , Partula V , Le Moyec L , Srour B , Fiolet T , Latino-Martel P , Kesse-Guyot E , Zelek L , Savarin P , Touvier M
Published: February 2018

Background: Combination of metabolomics and epidemiological approaches opens new perspectives for ground-breaking discoveries. The aim of the present study was to investigate for the first time whether plasma non-targeted metabolomic profiles, established from a simple blood draw from healthy women, could contribute to predict the risk of developing breast cancer within the following decade and to better understand the etiology of this complex disease.

Methods: A prospective nested case-control study was set up in the SU.VI.MAX cohort, including 206 breast cancer cases diagnosed during a 13y follow-up, and 396 matched controls. Non-targeted NMR metabolomic profiles were established from baseline plasma samples. Multivariable conditional logistic regression models were computed for each individual NMR variable and for combinations of variables derived by principal component analysis.

Results: Several metabolomic variables from 1D NMR spectroscopy were associated with breast cancer risk. Women characterized by higher fasting plasma levels of valine, lysine, arginine, glutamine, creatine, creatinine, and glucose and lower plasma levels of lipoproteins, lipids, glycoproteins, acetone, glycerol-derived compounds and unsaturated lipids had a higher risk of developing breast cancer. P-values ranged from 0.00007 (ORT3vsT1=0.37[0.23-0.61] for glycerol-derived compounds) to 0.04 (ORT3vsT1=1.61[1.02-2.55] for glutamine).

Conclusion: This study highlighted associations between baseline NMR plasma metabolomic signatures and long-term breast cancer risk. These results provide interesting insights to better understand complex mechanisms involved in breast carcinogenesis and evoke plasma metabolic disorders favorable for carcinogenesis initiation. This study may contribute to develop screening strategies for the identification of at-risk women for breast cancer well before symptoms appear.

Citation Format: Lécuyer L, Victor Bala A, Deschasaux M, Bouchemal N, Nawfal Triba M, Vasson M-P, Rossary A, Demidem A, Galan P, Hercberg S, Partula V, Le Moyec L, Srour B, Fiolet T, Latino-Martel P, Kesse-Guyot E, Zelek L, Savarin P, Touvier M. NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing 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 P1-02-01.
Abstract P1-02-04: Not presented
Authors: Reis J , Dale I , Logullo A , Brentanni MM , Junior TT , Waitzberg D , Ravacci G
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-02-09: Targeting breast cancer stem cell state equilibrium through modulation of redox signaling
Authors: Luo M , Shang L , Brooks M , Jiagge E , Zhu Y , Conley S , Fath MA , Harouaka R , Merajver SD , Spitz DR , Wicha MS
Published: February 2018

Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis and redox metabolism. Metabolic/Oxidative stress generated by 2DG/H2O2 or hypoxia promotes ROSlo M-BCSCs transition to their ROShi E-state. This transition is reversed by the antioxidant N-acetyl cysteine and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust expression of NRF2/NFE2L2 and a wide variety of NRF2 downstream antioxidant responsive genes including the family of drug transporters and detoxification enzymes, NADPH production as well as the thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Suppression of NRF2 activity by a small-molecular inhibitor Trigonelline or shNRF2 mediated knockdown significantly decreased ALDH+ E- but not CD24-CD44+ M-BCSCs. This specific vulnerability of E-BCSCs to the inhibition of NRF2-mediated antioxidant defenses was also observed following inhibition of the downstream TXN and GSH antioxidant pathways, which promotes ROS-mediated differentiation and subsequent apoptosis of E-BCSCs. Co-inhibition of glycolysis and TXN/GSH pathways synergistically suppressed tumor growth and tumor initiating potential in two patient-derived xenograft models of triple negative breast cancer by eliminating both M- and E-BCSCs. Together, our studies reveal novel cellular and molecular mechanisms demonstrating how modulation of redox signaling regulates the equilibrium of two distinct BCSC states. These studies define the metabolic vulnerabilities of M- and E-BCSCs, and also provide a novel therapeutic approach to collectively target these distinct CSC states. As the CSC state equilibrium may be similarly regulated across a spectrum of tumors with diverse oncogenic drivers, this approach may have broad therapeutic applicability.

Citation Format: Luo M, Shang L, Brooks M, Jiagge E, Zhu Y, Conley S, Fath MA, Harouaka R, Merajver SD, Spitz DR, Wicha MS. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling [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 P1-02-09.
Abstract P1-03-01: Withdrawn
Authors: Wehde B , Triplett A , Raedler P , Wagner K-U
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-03-08: Withdrawn
Authors: Guerra E , Trerotola M , Relli V , Pedicone C , D' Amore A , Alberti S
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-03-09: Not presented
Authors: Sun H , Zhao Y , Chen M , Jin W
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-03-11: Withdrawn
Authors: Kuruppu AI , Stocks MJ , Bradshaw TD
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-06-03: Breast cancer-specific survival (BCSS) in SEER patients with 21-gene Recurrence Score® (RS) results <11 classified as prognostic stage IA by new 8th edition AJCC staging manual
Authors: Baehner FL , Petkov VI , McCullough D , Shak S
Published: February 2018

Introduction: The 8th edition of the AJCC Staging Manual added molecular features for the first time and now includes ER, PR, HER2, and the 21-gene assay for prognostic staging. We obtained real-world evidence of BCSS by age, tumor size, and grade in a population-based SEER analysis of N0, HR+, HER2-negative breast cancer and RS <11 (tumor size up to 5 cm) to obtain more detailed information on clinically “unfavorable” subgroups.

Methods: RS results were provided to SEER registries as mandated by their methods for linkage (Petkov npj Breast Cancer 2016). Patients (pts) with RS <11 and size up to 5 cm were eligible if N0, HR+, HER2-negative, had no prior malignancy, and were diagnosed between Jan 2004 and Dec 2012 (SEER survival updated through 2013). 5-year BCSS was estimated using actuarial methods.

Results: 9,304 pts had RS <11 (19% of those meeting all other eligibility), with median follow-up of 40 months. Median age was 59 y, with 22% <50 y and 16% ≥70 y. Tumor size was >2 cm in 21% of pts. Tumor grade was moderate in 54% and poor in 8% of pts. Overall, 5-year BCSS for pts with RS <11 was 99.6% (95% CI 99.4%, 99.7%), with reported chemotherapy (CT) use in 3.3% of pts. In contrast, BCSS for pts with RS >25 and RS ≥31 was 3.5% and 4.7%, respectively, with frequent CT use. 5-year BCSS for important clinicopathologic subgroups show high 5-year BCSS despite “unfavorable” age, tumor size, and grade (Table).

5-y BCSS for RS <11, by Clinicopathologic FactorsRS <11 and Age <50 yRS <11 and Tumor Size 2.1-5.0 cmRS <11 and Poor Tumor GradeN (% of N with CT ‘Yes’)5-y BCSS (95% CI)N (% of N with CT ‘Yes’)5-y BCSS (95% CI)N (% of N with CT ‘Yes’)5-y BCSS (95% CI)2009 (6.2%)100% (100%, 100%)1976 (5.5%)99.3% (98.5%, 99.7%)686 (5.8%)99.5% (97.9%, 99.9%)

Conclusions: In this SEER population-based study, pts with RS <11 had a wide range of clinicopathologic features. 5-year BCSS was high (>99%), regardless of age, tumor size, or grade. These results support the new AJCC staging criteria that classify N0, HR+, HER2-negative pts with RS <11 and tumor size up to 5 cm as having Prognostic Stage IA disease.

Citation Format: Baehner FL, Petkov VI, McCullough D, Shak S. Breast cancer-specific survival (BCSS) in SEER patients with 21-gene Recurrence Score® (RS) results <11 classified as prognostic stage IA by new 8th edition AJCC staging manual [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 P1-06-03.
Abstract P1-07-02: Withdrawn
Authors: Rutgers E , Aalders K , Poncet C , Bogaerts J , Delaloge S , Rubio I , Thompson A , Tryfonidis K , van 't Veer L , Piccart M , Cardoso F
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-07-10: Molecular subtypes of triple negative breast cancer have different sensitivity signature to established chemotherapy agents
Authors: Győrffy B , Nagy Á , Santarpia L , Hatzis C
Published: February 2018

Background: Triple negative breast cancer (TNBC, ER/PR/HER2 negative) patients have the worst prognosis among all breast cancer patients. Recently, six molecular subtypes have been proposed to sub-divide TNBC into clinically relevant sub-cohorts. It is unknown whether these molecular subtypes have different sensitivity against known chemotherapy agents. Here, we identified the cross-section of predictive and prognostic genes in a large TNBC dataset.

Methods: An integrated database comprising 2,071 TNBC patients with transcriptome-level gene expression data and clinical follow-up was set up from 52 different GEO and EGA datasets. The database included n=418 basal-like 1, n=170 basal-like 2, n=465 immunomodulatory, n=384 mesenchymal, n=207 mesenchymal stem-like, and n=427 luminal androgen receptor samples. The prognosis was computed for all genes (n=54,675) in each of the six subtypes separately using Cox proportional hazards regression. Another database (n=1,641) was set up for tumors with known therapy response as defined by pathological complete response (PCR) – in this, the correlation to response against a taxanes/anthracycline chemotherapy was computed using Mann-Whitney analysis. The overlap between the two datasets was determined at p<0.0001.

Results: The proportion of responder patients was lowest in basal like 2 subtype. There were more genes significant for response to anthracyclines (n=6,118) than to taxanes (n=3,927). When comparing each subtype separately, most genes were prognostic in basal-like 1 and luminal androgen receptor subtypes (n=73/110 and n=73/111 respectively for taxane/anthracycline response genes). Almost no genes were overlapping to the immunmodulatory and mesenchymal stem-like subtypes (n=8/14 and n=3/7, respectively). When comparing anthracycline and taxane treatment across all six subtypes, there was no significant difference. We have to note that the different sample sizes in the different TNBC cohorts provide different power to detect an association.

Discussion: Based on our results, TNBC tumors in the basal-like 1 and luminal androgen receptors are most likely to benefit from chemotherapy while there is no difference for the selection between the two most common agents.

Citation Format: Győrffy B, Nagy Á, Santarpia L, Hatzis C. Molecular subtypes of triple negative breast cancer have different sensitivity signature to established chemotherapy agents [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 P1-07-10.
Abstract P1-07-27: Prognostic value of programmed death 1/Programmed death ligand 1/ mammalian target of rapamycin/Rictor/Tuberin in human breast cancer
Authors: Uhercik M , Sanders AJ , Owen S , Davies EL , Sharma AK , Jiang WG , Mokbel K
Published: February 2018

Background:The Mammalian Target of Rapamycin (mTOR) regulates a multitude of cellular processes including metabolism, proliferation and growth. It is known to form two multi-protein complexes - complex 1 (mTORC1) and complex 2 (mTORC2) with Raptor and Rictor being their core proteins vital for their integrity.

Tuberin, the product of the Tuberous Sclerosis Complex gene 2, TSC2, has been characterized as a tumour suppressor and negatively regulates the mTOR pathway.

Programmed Death 1 (PD-1), a transmembrane protein particularly expressed on the surface of tumour cells, acts as an immune checkpoint receptor. Together with its ligand Programmed Death Ligand 1 (PDL-1) they form a pathway which when activated influences anti-tumour immunity and supresses anti-tumour adaptive responses. The expression of PD1/PDL-1 is lightly regulated by the mTOR pathway.

We investigated the value of expression patterns of all these molecules in breast cancer as potential prognostic factors.

Materials and Methods: Quantitative PCR (qPCR) analysis was used to determine the transcript expression profile of the five genes of interest (PD-1, PDL-1, mTOR, Rictor and Tuberin) in 128 breast cancer specimens.The correlation between PD-1 or PDL-1 with mTOR, Rictor and Tuberin was assessed using the Spearman Rank Order Correlation. Subsequently, a combined analysis was performed, where the influence of favourable expression in relation to patient overall (OS) and disease free survival (DFS) using the Kaplan Meier survival curves and multivariate analysis.

Results: The mRNA expression of the molecules showed a varying degree of association with the clinicopathological parameters. PD-1 transcript expression showed a significant correlation with mTOR expression (p < 0.001). PDL-1 transcript expression was seen to correlate with mTOR (p < 0.001), Rictor (p < 0.001) and Tuberin (p < 0.01) transcript expression. However, when the expression profile was analysed using an integrated expression score, the combined predictive value for the clinical outcome of the five genes was highly significant in terms of OS (p < 0.001) and DFS (p = 0.001), and was found to be an independent prognostic factor (p<0.001) for breast cancer related death using a multivariate analysis.

Conclusions: Our study identifies a molecular signature of 5 genes as a powerful prognostic predictor of OS and DFS in patients with breast cancer.

Citation Format: Uhercik M, Sanders AJ, Owen S, Davies EL, Sharma AK, Jiang WG, Mokbel K. Prognostic value of programmed death 1/Programmed death ligand 1/ mammalian target of rapamycin/Rictor/Tuberin in human 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 P1-07-27.
Abstract P1-07-29: Clinicopathologic characteristics and prognostic factors of pure mucinous breast cancer
Authors: Gwark SC , Lee JW , Lee SB , Sohn G , Kim J , Chung IY , Kim HJ , Ko BS , Son BH , Ahn SH
Published: February 2018

Background: Mucinous carcinoma of the breast is a uncommon particular type of breast cancer and comprises approximately 4% of all invasive breast cancers. It is charactarized by abundant extracellular mucin production and present a more favorable prognosis than IDC-NOS. Pathologically, mucinous carcinoma is divided into two subtypes : pure and mixed. In this study, we reviewed the clinicopathologic characteristics and prognostic factors of pure mucinous carcinoma.

Methods: We reviewed the 23 years cumulative data of pure mucinous breast cancer patients from database of the Breast Cancer Center at ASAN medical center, Korea, between 1989-2011, retrospectively. Total 386 pure mucinous carcinoma cases were reviewed to analyze clinicopathologic characteristics and prognosis.

Result: Total of 386 patients with pure mucinous breast cancer were identified. Mean age was 46.7. 149 patients underwent modified radical mastectomy and 236 underwent breast-conserving therapy. The T-stage was T1 in 187 patients, T2 in 178 patients, T3 in 17 patient and T4 in 4 patients. Node negative was 325 and node positive was 61. Estrogen receptor was positive in 342 and negative in 29. Progesterone receptor was positive in 276 and negative in 95. HER-2 was positive in 47 and negative in 273. 152 patients received adjuvant chemotherapy and 240 patients received adjuvant radiotherapy. 351 patients received hormone therapy and among these patients, 231 patients were treated with Tamoxifen alone, 81 were Tamoxifen with ovarian function suppression, 37 were AI only and one patient was ovarian function suppression only. The 5 year disease free survival rate was 93.3%, 5 year cancer specific survival rate was 98.2% and 5 year overall survival rate was 96.6%. Univariate analysis showed that ER status, nodal status and Her2 status were appear to be prognostic factor of Disease free survival rate. Using Cox regression, result of multivariate analysis revealed that only nodal status is the most significant prognostic factor for survival rate.

Conclusions: Pure mucinous carcinoma of the breast is a rare subtype with a favorable prognosis. Nodal status rather than ER status, Her2 status are considered to be the most significant prognostic factor of pure mucinos breast cancer.

Citation Format: Gwark SC, Lee JW, Lee SB, Sohn G, Kim J, Chung IY, Kim HJ, Ko BS, Son BH, Ahn SH. Clinicopathologic characteristics and prognostic factors of pure mucinous 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 P1-07-29.
Abstract P1-07-33: Impact of family history of breast and/or ovarian cancer in triple negative breast cancer
Authors: Morante Z , De la Cruz-Ku G , Pinto J , Enriquez D , Lujan M , Luque R , Eyzaguirre E , Saavedra A , Fuentes H , Neciosup S , Gomez H
Published: February 2018

Background: A family history of breast and/or ovarian cancer (FHBOC) is a risk factor for breast cancer. The influence of FHBOC in the prognosis of triple-negative breast cancer (TNBC) is controversial. The aim of this study was to analyze the impact of FHBOC on the prognosis in TNBC patients.

Methods: We retrospectively reviewed a database of patients diagnosed of TNBC (period 2000-2014) and treated at “Instituto Nacional de Enfermedades Neoplasicas”. The patients were divided into two groups: with FHBOC and non-FHBOC. The clinical features and prognosis between groups were compared. Disease-free survival (DFS) and overall survival (OS) differences were calculated by the Kaplan-Meier Method and differences were evaluated by the Log- Rank test. Prognostic factors were identified by the Cox regression analysis.

Results: Overall, 266 out of 2007 TNBC patients, had +FHBOC (13.3%). The median age for the general population was 49 years. Compared with the non-FHBOC group (51.1%), the 43.8% +FHBOC were premenopausal. Prevalence of +FHBOC in a first-, second- and a third-degree relative was 26.8%, 28.5%, and 44.7%, respectively. Regarding histological subtype, invasive ductal carcinoma was the most prevalent (93.5%). Clinical stages (CS) II/III was more frequent in both groups (86.3 vs. 86.1). A total of 59% of FHBOC patients underwent surgery and 52% for non-FHBOC (p=0.029- Conservative 41.1 vs. 30.7 - Mastectomy 58.9 vs. 69.3). The median of follow-up was 9 years. DFS rate was higher in FHBOC patients (53.6% vs. 42.9%, p=0.001). OS was significantly better In the FHBOC group (Table 1). In the multivariate analysis, poor prognosis variables to DFS were an advanced age at diagnosis (≥50 years) (p=0.006) and higher clinical stage (CS I vs. CS III, p<0.001) while chemotherapy (CT) and radiotherapy (RT) were associated with an improved DFS. In regard to the OS, FHBOC was associated with a better prognosis (HR:0.77, 95%CI:0.62- 0.95, p=0.016).

Conclusion: Our results showed a better prognosis in TNBC patients with family history of breast and/or ovarian cancer in terms of DFS and OS.

Table 1. +FHBOC group (DFS/OS rates) +FHBOCnon-FHBOCTotalPDFS (%)    5-years7162630.03210-years635052 OS (%)    5-years665455<0.00110-years584750 

Citation Format: Morante Z, De la Cruz-Ku G, Pinto J, Enriquez D, Lujan M, Luque R, Eyzaguirre E, Saavedra A, Fuentes H, Neciosup S, Gomez H. Impact of family history of breast and/or ovarian cancer in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-33.
Abstract P1-07-34: Clinical outcomes of single versus double hormone receptor positive breast cancer patients treated with neoadjuvant chemotherapy
Authors: Raphael J , Nofech-Mozes S , Trudeau ME
Published: February 2018

Purpose

This study aimed to evaluate and compare tumor response rates and survival outcomes between single and double hormone receptor (HR) positive (+) [Estrogen Receptor (ER+)/Progesterone Receptor (PR) negative (-) or ER-/PR+ versus ER+/PR+] breast cancer (BC) patients with any HER2 status treated with neoadjuvant chemotherapy at a single institution

Methods

A retrospective review was conducted using the Sunnybrook “Biomatrix” database to identify eligible patients. A multivariable logistic regression analysis (MLR) was performed to assess the association between HR status (single or double HR+) and pathologic complete response (pCR) rates at surgery. A Kaplan-Meier method was used to estimate Disease Free Survival (DFS) and a log-rank test was used to compare DFS between 3 subgroups of patients: single or double HR+ and HR negative patients

Results

Three hundred and four BC patients were identified and included in the analysis with a median follow up of 43.3months (Q1-Q3: 28.7-61.1) and a mean age of 49.7 years (Standard deviation 10.9). Forty seven percent (47/101), 31% (11/36) and 14% (24/167) of patients with HR negative, single HR+ and double HR+ disease achieved a pCR respectively (X2 test <0.0001). In a MLR analysis, HR status and HER2 status were associated with pCR rates. Compared to HR negative patients, patients with double HR+ disease were less likely to achieve pCR (Odd ratio (OR):0.14, 95%CI 0.06-0.31, p<0.0001) while single HR+ patients did not differ (OR:0.51, 95%CI 0.19-1.4). The association between HR+ status (single versus double HR+) and pCR rates compared to HR negative patients remained the same in subgroup analyses of HER2+ and HER2 negative patients separately. No difference in survival (DFS) was seen between the 3 subgroups of patients: HR negative, single and double HR+ patients.

Conclusion

BC patients with single HR+ disease behave differently than double HR+ patients in terms of likelihood of achieving pCR after neoadjuvant chemotherapy and do not differ from HR negative patients. This difference does not translate into a difference in DFS. Prospective studies are needed to validate these findings before considering different treatment strategies for these 2 subgroups of HR+ BC patients.

Citation Format: Raphael J, Nofech-Mozes S, Trudeau ME. Clinical outcomes of single versus double hormone receptor positive breast cancer patients treated with neoadjuvant chemotherapy [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 P1-07-34.
Abstract P1-08-03: Withdrawn
Authors: Sohn J , Sharma P , Dirix L , Allison J , Ben Y , Kataria R , Ferro S , Asubonteng K , Oh D-Y
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-08-06: Not presented
Authors: Nagarajan D , Durrant L , Christensen D , Pockley AG , McArdle S
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-09-09: Efficacy of estrogen receptor β agonists in the prevention of breast cancer progression to therapy resistance
Authors: Ramasamy K , Samayoa C , Krishnegowda NK , Vadlamudi RK , Tekmal RR
Published: February 2018

Estrogen plays an important role in the initiation and progression of breast cancer (BCa). Approximately, 70% of breast tumors are estrogen receptor (ER) positive at the time of presentation. Endocrine therapy using aromatase inhibitors (AI), or anti-estrogen (AE) molecules are widely used for treating ER+ve BCa. However, their efficacy is limited by intrinsic and acquired therapy resistance and most patients develop resistance to these drugs. The transcriptional effects of estrogen are mediated by two ERs (ERα and ERβ) and both are expressed in normal breast tissue. Unlike ERα, ERβ functions as tumor suppressor. However, role of ERβ specific agonists in the prevention of BCa progression remains elusive. In this study, we investigated the effectiveness of two ERβ agonists (S-Equol and LY500307) in the prevention of BCa progression using endocrine therapy sensitive (MCF7-aro) and letrozole resistant (MCF7-aro-LTLT) cells. Our results demonstrated that treatment with ERβ agonists inhibit short-and long-term growth of both endocrine therapy sensitive and resistant BCa cells. In addition, ERβ agonists treatment inhibited invasion and migration of both MCF7-aro and MCF7-aro-LTLT cells. Importantly, cell cycle analysis revealed that ERβ agonists induced cell cycle arrest. Our gene microarray analysis demonstrated that both ERβ agonists significantly modulated genes involved in the cell cycle progression, DNA replication and cell death pathways. Further, gene enrichment analysis of differentially expressed genes revealed that genes involved in the cell cycle checkpoints emerged as significant pathway modulated by ERβ agonists treatment in MCF7-aro cells. Interestingly, in letrozole-resistant MCF7-aro cells, DNA replication was significantly affected by ERβ agonists treatment. Pathway analysis also identified enrichment for chemokine signaling pathways. We confirmed pathway analysis by qRT-PCR and western blot analysis. Accordingly, treatment of in vivo syngeneic xenografts with ERβ agonists significantly inhibited BCa progression. Collectively, these results from this study suggest that ERβ agonists have potential to prevent the progression of BCa progression.

Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Efficacy of estrogen receptor β agonists in the prevention of breast cancer progression to therapy resistance [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 P1-09-09.
Abstract P1-13-14: Triple positive breast cancer ; a distictive subtype and consideration of systemic therapeutic approach
Authors: Kim JS , Kim YS , You SH
Published: February 2018

Introduction: Triple positive breast cancer is one of intrinsic subtype in breast cancer that is defined namely, ER/PR/Her2 positive tumors. It has multiple strategies for systemic therapy according to the characteristics of hormonal and anti-HER2 responsiveness. Each targeted therapy plays cross-talks between HER-2 and estrogen receptor signaling pathway resulting in endocrine resistance and anti Her2 resistance.

Methods: We compared the triple positive subtype to the other breast cancer intrinsic subtypes to distinguish the uniqueness in their position among other breast cancer subtypes using retrospective analysis of two different cohorts; Korea Breast Cancer Society (KBCS) Breast cancer registry data (N=31266, Jan. 2006 – Dec. 2010) and database from St. Mary`s hospital Breast cancer registry (N=2216, Apr. 2009 – Mar. 2016).

Results: Median follow up duration of 76 months in KBCS cohort (2006-2010) showed the overall survival graph of triple positive breast cancer located in the middle in between Luminal A intrinsic subtype and HER2 enriched subtype(P<.001). Also HER2 directed trastuzumab therapy did not improve the overall survival in triple positive breast cancer patients (P=.899) in contrast to the improved overall survival using trastuzumab therapy in HER2 enriched subtype (P=.018). Like the preceding results, CMC breast cancer data showed the similar results in recurrence free survival (P<.001). and no recurrence free survival improvement using trastuzumab therapy in triple positive breast cancer patient during the median follow up of 33 months (P=0.800).

Conclusion:

1) Anti-HER2 therapy seems less beneficial in Triple positive breast cancer subtype regardless of breast cancer stage.

2) Triple positive breast cancer may require different therapeutic approaches

3) Other targeted agents (mTOR inhibitor, CDK4/6 inhibitor, PIK3CA inhibitor) can be a substitute option for the Trastuzumab therapy in triple positive breast cancer.

Citation Format: Kim JS, Kim YS, You SH. Triple positive breast cancer ; a distictive subtype and consideration of systemic therapeutic approach [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 P1-13-14.
Abstract P1-15-04: Outcome of small (≤1 cm), node-negative breast cancer
Authors: Muzaffar M , Namireddy P , Naqash R , Wong J , Vohra N
Published: February 2018

Background: Screening mammogram has resulted in increased diagnosis of very small breast cancers, especially less than 1 cm node negative. These small tumors have excellent prognosis with cancer-specific survival rates as high as 90% to 95%. This study evaluates outcome in different subtypes of very early breast cancer in a national population database.

Method: Patients with stage I breast cancer, tumor ≤ 1cm with negative nodes (T1aN0 (<0.5cm), T1bN0 (≥ 0.5cm to ≤ 1cm) diagnosed between 2006 and 2011 were identified in the SEER database. We excluded patients with missing biomarker information. Treatment outcome and prognostic factors for disease-specific survival (DSS) and overall survival (OS) were evaluated.

Results: We identified 70,543 cases and included 54,796 patients with stage T1aN0M0 and T1bN0M0 in the final analysis. The mean age was 62.09 yrs. (CI 95% 62.2-61.99), 84% are white, 7% black and 7% others.89% had ER positive tumor, 11% ER negative and 3% had Her 2 positive tumors.71% of patients had T1b (≤ 1cm). The 5-year disease specific survival (DSS) and overall survival (OS) for patients with stage T1aN0, T1bN0 was 98.7% and 93.7%, respectively. Estrogen receptor (ER) positive tumors were associated with improved 5-yr DSS 99% vs. 96% in ER negative (p<0.0001) and OS in ER positive 94% vs. 92%( p<0.0001). Among white patients 5-yr DSS was 98.8% and OS was 93.7% while 5yr-DSS was 94%, OS 91.5% among black vs. 5-yr DSS 99% and OS 96.3% in others (Asian or Pacific Islanders, AI), (p<0.0001). Tumor subtype was not associated with significant difference in outcome but T1a tumor was associated with OS 94.5% vs. 93.4% with T1b tumors (p<0.0001) On cox model analysis factors which correlated with prolonged DSS and OS are race (p<0.0001), older age (p<0.0001), ER positivity (p<0.0001) and tumor less than 5mm (p=0.0006).

Conclusions: Very early breast cancer is associated with excellent outcome but has some heterogeneity. Nonwhite/Non Black race was associated with better survival compared to white and black patients. ER positive tumors, and older age were also associated with better outcome. This data while reassuring also brings into question the overtreatment of this disease subset. One of the limitations of this dataset is lack of details of systemic therapy administered. Conventional prognostic factors are not sufficient to risk stratify very early breast cancer and molecular profiling may help identify patients who will need adjuvant treatment.

Citation Format: Muzaffar M, Namireddy P, Naqash R, Wong J, Vohra N. Outcome of small (≤1 cm), node-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-15-04.
Abstract P2-02-01: Withdrawn
Authors: Turner NC , Garcia-Murillas I , Chopra N , Beaney M , Cutts RJ , Swift C , Kriplani D , Morden J , Hrebien S , Comino-Mendez I , Afentakis M , Bliss J , Skene A , Wheatley D , Russell S , Evans A , Dowsett M , Smith IE
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P2-02-17: Circulating tumor DNA analysis with ultra-high sensitivity sequencing in metastatic breast cancer
Authors: Garcia-Murillas I , Proszek P , Fribbens C , Yuan L , Bye H , Hubank M , Jiang J , Yuang S , Palma J , Johnston S , Ring A , Turner N
Published: February 2018

Introduction.

Circulating tumor DNA analysis has the potential to transform the clinical management of patients with breast cancer. We assessed the accuracy of ultra-high sensitivity ctDNA testing in patients with advanced breast cancer.

Methods.

From a prospective tissue collection study, we identified 25 patients with a contemporaneous metastatic tissue biopsy and plasma for ctDNA testing. Tumour DNA from the metastatic tissue biopsy was sequenced with a validated clinical hybrid capture panel, while plasma cell free DNA was sequenced with AVENIO ctDNA technology – a molecular barcoded duplex sequencing based on CAPPseq technology. Sample collection is on-going and results from the full concordance series will be presented at the conference.

Results.

Circulating tumour DNA was detectable in 87% (20/23) of patients, with at least one variant from tissue sequencing identified in plasma. There was overall high agreement between tissue and plasma sequencing. The sensitivity of plasma testing for variants identified in tumour, positive percent agreement, was 75% (24/32). Plasma testing revealed a diversity of sub-clonal mutations including polyclonal ESR1, polyclonal FGFR2 and FGFR3 mutations, rare KRAS mutations, and TSC1 and MSH2 inactivating mutations.

Conclusions.

Circulating tumour DNA testing with molecular barcoded duplex sequencing offers high sensitivity for tumour variant detection. The extent of sub-clonal resistance mutations identified emphasises the genetic diversity of advanced breast cancer.

Citation Format: Garcia-Murillas I, Proszek P, Fribbens C, Yuan L, Bye H, Hubank M, Jiang J, Yuang S, Palma J, Johnston S, Ring A, Turner N. Circulating tumor DNA analysis with ultra-high sensitivity sequencing in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-17.
Abstract P2-03-09: An institutional look back: Maximizing the utility of MammaPrint® in invasive breast cancer diagnostics without breaking the bank
Authors: Cross AW , McEvoy JR
Published: February 2018

Background: Subtyping of invasive breast cancer utilizing immunohistochemical stains for estrogen receptor, progesterone receptor, and HER2, with or without the proliferation marker Ki-67, is the current standard of care employed by pathologists. The development of the BluePrint® molecular subtyping assay by Agendia, a microarray-based gene expression test used in conjunction with MammaPrint, to molecularly subtype and assess recurrence risk in early-stage breast cancer, has breast surgeons and oncologists challenging the status quo.

Study Objectives: With increasing emphasis placed of proper use of declining resources, the current study aimed to determine parameters in which such testing has the greatest added value.

Materials and Methods: All invasive breast cancer biopsies and resection specimens with formalin fixed paraffin embedded tissue sent for testing at Agendia Genomics Laboratory from April 2015 to May 2017 were reviewed in an institutional look back. 87 cases were reviewed and conventional immunohistochemical cancer profiling, tumor size, and grade were compared with MammaPrint prognostic reports.

Results and Discussion: Of the 87 cases compared, 67 (77%) showed concordance between immunohistochemical and molecular subtyping. Of the 20 discordant cases, 13 (65%) were subtyped as low risk luminal A by Mammaprint/BluePrint despite demonstrating high risk clinicopathologic features including larger size (average 2 cm vs overall average 1.4 cm), higher grade (1 low grade, 11 intermediate grade, and 1 high grade vs totals of 36 low grade, 42 intermediate grade, and 20 high grade), and increased proliferation indices. 3 (15%) of discordant cases revealed HER2 amplification by fluorescence in situ hybridization. Near complete agreement was found among basal subtype and Luminal A tumors with Ki-67 less than 12%, indicating the lack of added value among these cases.

Conclusion: Study results validate the limited role of MammaPrint/BluePrint in cases of invasive breast cancer. Specifically, the greatest value of MammaPrint/BluePrint was recognized in luminal subtypes with intermediate grade and proliferation indices ranging from 12 – 29%.

Citation Format: Cross AW, McEvoy JR. An institutional look back: Maximizing the utility of MammaPrint® in invasive breast cancer diagnostics without breaking the bank [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-09.
Abstract P2-05-03: Novel driver genetic alterations in MYB-NFIB-negative breast adenoid cystic carcinomas
Authors: Kim J , Geyer FC , Martelotto LG , Ng CKY , Lim RS , Selenica P , Li A , Pareja F , Fusco N , Edelweiss M , Mariani O , Badve S , Vincent-Salomon A , Norton L , Reis-Filho JS , Weigelt B
Published: February 2018

Introduction: Breast adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer associated with an indolent clinical behavior. AdCCs provide a clear example of genotypic-phenotypic correlation with the majority harboring the MYB-NFIB fusion gene. In this study, we sought to identify alternative driver genetic alterations in breast AdCCs lacking the MYB-NFIB fusion gene.

Methods: Nucleic acids obtained from four breast AdCCs lacking the MYB-NFIB fusion gene as defined by reverse transcription (RT)-PCR and/or fluorescence in situ hybridization (FISH) were subjected to RNA-sequencing (n=3), whole-genome (n=2) and/or targeted (n=1) massively parallel sequencing. Sequencing data were analyzed using state-of-the-art bioinformatics algorithms, and potential alternative driver genetic alterations were validated using orthogonal sequencing and molecular pathology methods.

Results: RNA-sequencing revealed the presence of MYBL1-ACTN1 or MYBL1-NFIB fusion genes in two breast AdCCs, which were validated by whole-genome sequencing and/or MYBL1 FISH analysis. Both MYBL1 fusion gene-positive cases were found to overexpress MYBL1 as defined by quantitative RT-PCR analysis. In the third MYB-NFIB-negative breast AdCC studied, a high-level MYB gene amplification coupled with overexpression of MYB at the mRNA and protein levels was identified. In the fourth breast AdCC, which expressed high levels of MYB, whole-genome and RNA-sequencing revealed no definite alternative driver alteration, however, a MYBL2 intronic mutation was found in this case, which was associated with high levels of MYBL2 mRNA expression. In this case, single sample gene set enrichment analysis revealed activation of pathways similar to those activated in AdCCs harboring the MYB-NFIB or MYBL1 fusions genes.

Conclusion: We demonstrate that in breast AdCCs lacking the MYB-NFIB fusion gene MYBL1 rearrangements and MYB amplification are likely alternative driver genetic events. Given that activation of MYB/MYBL1 and their downstream targets can be driven by the MYB-NFIB fusion gene, MYBL1 rearrangements, MYB amplification or other yet to be validated mechanisms (e.g. MYBL2 non-coding mutations), our findings further suggest that breast AdCCs constitute a convergent phenotype.

Citation Format: Kim J, Geyer FC, Martelotto LG, Ng CKY, Lim RS, Selenica P, Li A, Pareja F, Fusco N, Edelweiss M, Mariani O, Badve S, Vincent-Salomon A, Norton L, Reis-Filho JS, Weigelt B. Novel driver genetic alterations in MYB-NFIB-negative breast adenoid cystic carcinomas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-03.
Abstract P2-05-12: Not presented
Authors: Shao X , Zheng Y , Zou W , Li G , Huang P , Wang X
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-05-15: Oncotype DX Breast Recurrence Score®: Real-life utilization among node positive patients in Ontario
Authors: Richardson R , Macchiusi A , Bhasin A , Takizawa C
Published: February 2018

Aims: The 21-gene Oncotype DX (ODX) Recurrence Score (RS) has been extensively validated to predict the risk of distant recurrence and the magnitude of response to hormone and chemotherapy in patients with ER+ N0 and N+ (up to 3 positive nodes) HER2- early stage breast cancer. Outcomes data from multiple large studies further confirm the assays clinical validity and utility. The test is currently reimbursed in Ontario for N0 but not for N1 patients. In 2016, a market access program has been initiated to address lack of data in current clinical practice in Ontario among N1 patients. It collects data assessing the real-life use of the test in Ontario and its impact on treatment decision. This analysis presents the interim analysis until end of May 2017.

Methods : The program allows for prospective data collection in key breast cancer centers in Ontario. Through an online dedicated platform patient data are collected including classical pathological and clinical parameters (e.g. histology, tumor grade and size, ER, PR, and HER2 status), patients age, ODX Recurrence Score results and recommended treatment both before and after the test results have been reported.

Results: A total of 7 qualified breast cancer centers or network of centers participated in the program and collected 90 cases so far. Study results demonstrated that ODX is used among a wide variety of patients profiles: 28% G1, 58% G2 and 14% of G3, 18% pre-, 12% peri- & 69% are post-menopausal, 20% are aged 40-49, 24% are 50-59, 29% are 60-69 and 26% are 70 and older, 3% tumor are <1cm, 38% are 1-<2cm, 52% are 2-<5cm and 7% tumor size are >5cm.

RS distribution is the following: <18 (67%), 18-30 (30%) and >30 (3%).

In addition, pre-ODX 90% of patients had a treatment recommendation for chemo-hormonotherapy (CT-HT). Post-testing, the number of patients recommended CT-HT decreased to 36%, highlighting that the test reduces unnecessary use of CT. In fact, the ODX led to an overall 54% net reduction in chemotherapy.

Conclusions: This real-life survey confirms that ODX provides critical information beyond clinical and pathological criteria. The assay changes treatment decisions among N+ patients in Ontario, sparing CT which could result in potential savings to the healthcare system.

Citation Format: Richardson R, Macchiusi A, Bhasin A, Takizawa C. Oncotype DX Breast Recurrence Score®: Real-life utilization among node positive patients in Ontario [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-15.
Abstract P2-07-03: Systematic characterization of kinase inhibitors reveals heterogeneity in responses by class and cell line
Authors: Mills CE , Subramanian K , Hafner M , Chung M , Boswell SA , Everley RA , Juric D , Sorger PK
Published: February 2018

Several publications have addressed concerns surrounding drug response screens by pointing out sources of variability and by presenting recommendations for better experimental methods and more robust analytical approaches. In the presented profiling effort, we integrated the latest advances in drug response measurement and focused on data diversity and quality rather than on breadth. We selected 32 breast cancer cell lines with a strong bias towards triple negative lines as well as 4 cell lines established from relevant patient-derived xenografts. We evaluated a panel of clinically relevant kinase inhibitors using a microscopy-based dose response assay to measure drug potency, and to quantify drug efficacy in terms of growth inhibition (GR metrics) and cell death. The use of the GR metrics to quantify drug sensitivity enabled us to identify and study differences between cytostatic and cytotoxic responses. This systematic dose response dataset is complemented by measurements of baseline transcript expression levels by mRNAseq, quantification of absolute abundance of ˜12,000 proteins, and relative phosphoprotein levels by shotgun mass spectrometry across all cell lines. Additionally, the baseline activity of transcription factors and kinases were inferred from the mRNA (using VIPER) and phosphoprotein (using kinase enrichment analysis) data, respectively. The complementarity of these multi-omics data has allowed us to address questions about the landscape of breast cancer cell lines such as: Where do the patient-derived lines lay relative to the conventional cell lines? How consistent are the landscapes defined by each dataset? How does integration across datasets provide mechanistic insight into signaling pathways that are active in each cancer subtypes? The measured and inferred baseline data were used to build predictors of the observed drug responses with the goal of identifying the biological processes responsible for the differences in sensitivity across drugs and cell lines. Overall the dataset that has been collected is a valuable resource for understanding drug response in triple negative breast cancer, and the molecular mechanisms that influence it.

Citation Format: Mills CE, Subramanian K, Hafner M, Chung M, Boswell SA, Everley RA, Juric D, Sorger PK. Systematic characterization of kinase inhibitors reveals heterogeneity in responses by class and cell line [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-03.