bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES6-1: How tumor metabolism contributes to the immunosuppressive microenvironment
Authors: Rathmell JC
Published: February 2018

Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that T cell subsets require distinct metabolic programs. The effector CD4 T cell fates (Th1, Th2, Th17) activate a highly glycolytic program. Regulatory CD4 T cells (Treg), in contrast, utilize a more oxidative metabolism and utilize lipids as a major fuel. These metabolic distinctions may allow new understanding of T cell function in tumors and approaches to manipulate immunity. We have now examined the metabolism of Treg in detail and found that FoxP3 itself can promote oxidative metabolism characteristic of Treg and that this is critical to maximize Treg suppressive capacity. Treg can be glycolytic and proliferative in vivo. We found, however, that glucose uptake and glycolysis impaired Treg stability. Thus, Treg regulate glycolytic and oxidative metabolism to balance proliferation and suppressive function. Conversely, the requirement of effector T cells for glucose uptake and glycolysis poses a barrier to inflammatory function in tumors. We have analyzed the metabolism of CD8 T cells in clear cell Renal Cell Carcinoma (ccRCC) and identified multiple metabolic defects. Importantly, bypassing these defects can enhance T cell function, demonstrating that metabolic alterations pose barriers to anti-tumor immunity. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector and regulatory populations.

Citation Format: Rathmell JC. How tumor metabolism contributes to the immunosuppressive microenvironment [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 ES6-1.
Abstract ES6-2: Do tumors overcome immune surveillance by blocking dendritic cell development
Authors: DeNardo DG
Published: February 2018

Tumors must evade immune-surveillance in order to progress. To this end, tumor-induced inflammation expands immune-suppressive immature granulocytes and monocytes, while limiting the functions of immune-stimulatory conventional dendritic cells (cDCs). cDC1s, a cDC subset, activate CD8+ T cells through antigen cross presentation and are marked by CD141 in humans and CD103 or CD8α in mice. cDC1s support anti-tumor CD8+ T cell responses, but cDC1 numbers are limited within the tumor environment. To understand how cDC1s are restricted in the tumor, we interrogated their development in the bone marrow (BM). We found the program responsible for the expansion of immature granulocytes and monocytes from progenitors in the BM is simultaneously suppressing the generation of cDC1s, decreasing the systemic numbers of cDC1s in breast and pancreatic cancer patients. We found that tumor-induced granulocyte stimulating factor (GCSF) mediates the down-regulation of the transcription factor IFN regulatory factor 8 (IRF8) in BM progenitors. IRF8 loss reprograms the BM progenitors, reducing their potential to develop into cDC1s. We demonstration, independent of monocyte and granulocyte expansion, that tumor-induced loss of cDC1s reduces the systemic ability to mount anti-tumor CD8+ T cell responses. Further, systemic decreases in cDC1s in breast cancer patients correlate with reduced response to chemotherapy. These data suggest a new mechanism of immune-escape whereby tumors down-regulate cDC1 differentiation from BM progenitors to impair anti-tumor CD8+ T cell immunity.

These data beg the question; are some patients unresponsive to immunotherapy because of tumor-induced impairments in dendritic cell development?

Citation Format: DeNardo DG. Do tumors overcome immune surveillance by blocking dendritic cell development [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 ES6-2.
Abstract ES8-1: Liquid biopsies in breast cancer - challenges and opportunities
Authors: Dawson S-J
Published: February 2018

Cell-free circulating DNA containing tumor-specific sequences can be identified in the plasma of cancer patients, providing a liquid biopsy alternative to tissue biopsies for monitoring cancer genetic changes over time. Circulating tumor DNA (ctDNA) analysis can allow real-time monitoring of tumor dynamics and treatment response from a simple blood test that is safe, reliable and easy to perform at regular intervals during therapy. Serial analysis of ctDNA provides a unique opportunity to study the evolving genomic landscape of a cancer during therapy, identify the early emergence of treatment resistance and guide targeted therapeutic decisions. The use of ctDNA for molecular disease monitoring has the potential to facilitate precision medicine and optimize cancer management across a range of malignancies. A summary of current approaches for ctDNA analysis will be presented, together with an overview of clinical applications for the use of liquid biopsies in breast cancer management.

Citation Format: Dawson S-J. Liquid biopsies in breast cancer - challenges and opportunities [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 ES8-1.
Abstract GS4-06: Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance
Authors: Couch FJ , Shimelis H , Hart SN , Moore RM , Thomas A , Lipton GB , Iversen E
Published: February 2018

Background: Germline genetic testing of individuals with a diagnosis of triple negative breast cancer, young age at diagnosis, or a family history of breast and/or ovarian cancer has led to the identification of many unique BRCA2 missense variants of uncertain significance (VUS). VUS in BRCA2 are predominantly missense mutations that have unclear relevance to breast, ovarian, and other cancers. Thus, patients found to have a germline BRCA2 VUS do not know if the variant is associated with high risks of these cancers similar to truncating mutations, intermediate risks more similar to CHEK2 mutations, or low risks of no clinical significance. Furthermore, it is unclear if germline BRCA2 VUS, or somatic VUS identified by tumor sequencing, are associated with hypersensitivity to selected DNA damaging and cross-linking agents.

Methods: We have used a homology directed repair (HDR) cell-based assay to characterize missense variants in the DNA binding domain (DBD) of BRCA2. The method has been validated using known pathogenic and known non-pathogenic BRCA2 missense variants and has 100% sensitivity (95% confidence interval (CI): 75.3%–100%) and 100% specificity (95% CI: 81.5%–100%) for pathogenic BRCA2 variants. A classifier of variant pathogenicity based on the mean and variances of the distributions of the HDR results of the known pathogenic and neutral variants has been established. We have also developed PARP inhibitor and cisplatin drug response assays for BRCA2 missense variants.

Results: Assessment of 207 BRCA2 missense variants, identified in public databases such as BRCA exchange and ClinVar, by the HDR assay identified 71 deleterious variants with >99% probability of pathogenicity, 116 neutral variants with >99% probability of neutrality, and 20 with hypomorphic activity and potentially intermediate risk. A combination of the functional data and sequence-based predictors of protein activity in a Bayesian prediction model resulted in classification of the deleterious variants as pathogenic cancer predisposing variants and the neutral variants as non-pathogenic with low clinical significance. The influence of the deleterious/pathogenic variants on PARPi and cisplatin response was also assessed.

Conclusion: The HDR assay is effective for characterization of BRCA2 VUS. The combination of functional data and in silico prediction models provides a robust tool for clinical annotation of BRCA2 VUS. HDR function of BRCA2 missense variants is strongly correlated with response to targeted therapy.

Citation Format: Couch FJ, Shimelis H, Hart SN, Moore RM, Thomas A, Lipton GB, Iversen E. Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance [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 GS4-06.
Abstract GS5-04: Prediction of occult invasive disease in ductal carcinoma in situ using deep learning features
Authors: Lo JY , Grimm LJ , Mazurowski MA , Baker JA , Marks JR , King LM , Maley CC , Hwang E-SS , Shi B
Published: February 2018

Background: Deep learning, especially deep convolutional neural network (CNN), has emerged as a promising approach for many image recognition or classification tasks, demonstrating human or even superhuman performance. Used as feature extractor, some pre-trained CNN models can match or surpass the performance of domain-specific, “handcrafted” features. In this study, we aim to determine whether deep features extracted from digital mammograms using a pre-trained deep CNN are prognostic of occult invasive disease for patients with ductal carcinoma in situ (DCIS) on core needle biopsy.

Materials and Methods: In this retrospective study, we collected digital mammography magnification views for 99 subjects with DCIS at biopsy, 25 of which were subsequently upstaged to invasive cancer. We utilized a deep CNN model that was pre-trained on non-medical images (e.g., animals, plants, instruments) as the feature extractor. Through a statistical pooling strategy, we extracted deep features at different levels of convolutional layers from the lesion areas, without sacrificing the original resolution or distorting the underlying topology. A multivariate classifier was then trained to predict which tumors contain occult invasive disease. This was compared to the performance of traditional “handcrafted” computer vision (CV) features previously developed specifically to assess mammographic calcifications. The generalization performance was assessed using Monte Carlo cross validation and receiver operating characteristic (ROC) curve analysis.

Results: Deep features were able to distinguish DCIS with occult invasion from pure DCIS, with an area under the ROC curve (AUC-ROC) equal to 0.70 (95% CI: 0.68-0.73). This performance was comparable to the "handcrafted" CV features (AUC-ROC = 0.68, 95% CI: 0.66-0.71) that were designed with prior domain knowledge.

Conclusion: In spite of being pre-trained on only non-medical images, the deep features extracted from digital mammograms demonstrated comparable performance to "handcrafted" CV features for the challenging task of predicting DCIS upstaging.

Acknowledgments: This work was supported in part by NIH/NCI R01-CQA185138 and DOD Breast Cancer Research Program W81XWH-14-1-0473.

Citation Format: Lo JY, Grimm LJ, Mazurowski MA, Baker JA, Marks JR, King LM, Maley CC, Hwang E-SS, Shi B. Prediction of occult invasive disease in ductal carcinoma in situ using deep learning features [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 GS5-04.
Abstract GS6-06: Identifying metastatic drivers in patient-derived xenograft models of triple negative breast cancer
Authors: Powell E , Shao J , Picon HM , Ge Z , Echeverria GV , Peoples M , Bristow C , Cai S , Tu Y , McCoy AM , Piwnica-Worms D , Draetta G , Edwards JR , Moulder SL , Symmans WF , Heffernan TP , Liang H , Piwnica-Worms H
Published: February 2018

Metastases are responsible for the vast majority of deaths due to breast cancer. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of metastasis and poor prognosis. We are employing patient derived xenograft (PDX) models of TNBC to identify drivers of metastasis. Tumor samples are obtained from the breast tumors of patients with TNBC and engrafted immediately into the humanized mammary fat pads of immune compromised mice. Lentiviral transduction was employed to express bioluminescent and fluorescent markers in two independent PDX models of TNBC. Using these models, we demonstrated that human breast tumors are capable of completing all stages of the metastatic cascade in mice, and metastatic lesions are observed in organs normally found in patients with metastatic breast cancer including lung, liver, bone, brain, and lymph nodes. Dynamic and reversible epithelial to mesenchymal transition (EMT) was observed as tumors metastasized to lung and were re-passaged to recipient mouse mammary glands. Lung metastases were isolated using bioluminescence imaging and lung metastasis gene expression signatures were generated. Metastasis signatures from two independent PDX models were compared to identify genes that were commonly de-regulated in lung metastases relative to corresponding mammary tumors. Comprehensive gain-of-function screens were then conducted in vivo to identify functional drivers of TNBC metastasis. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a metastatic driver in this screen. CEACAM5 mRNA and protein levels were elevated in lung metastases relative to corresponding mammary gland tumors in mice. In addition, we demonstrated that CEACAM5 expression was upregulated in the lung metastases of breast cancer patients, and its expression inversely correlated with patient survival. Our data indicate that the metastatic function of CEACAM5 is to promote growth of breast tumors in the lung by inducing MET (mesenchymal to epithelial transition).

Citation Format: Powell E, Shao J, Picon HM, Ge Z, Echeverria GV, Peoples M, Bristow C, Cai S, Tu Y, McCoy AM, Piwnica-Worms D, Draetta G, Edwards JR, Moulder SL, Symmans WF, Heffernan TP, Liang H, Piwnica-Worms H. Identifying metastatic drivers in patient-derived xenograft models of 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 GS6-06.
Abstract IS-2: The challenge of definition and adoption; perspective from the Middle East
Authors: Al Sukhun S
Published: February 2018

Cancer has become one of the leading causes of morbidity and mortality worldwide. The World Health Organization has warned the number of cancer diagnoses in the Middle East (ME) in the next two decades will nearly double unless authorities take action. This means the ME will have the highest relative increase of all regions in the world. Breast cancer is the most common cancer in ME (15%) and the second most common in terms of cancer related mortality (9%).

Across the world, the cost of healthcare is rising faster than economies are growing, creating the case for value based healthcare (VBHC), with value based medicine taking center stage. VBHC helps healthcare providers manage cost increases, make the best use of finite resources and deliver improved care to patients. The challenge for effective control of cancer is multifaceted. It mandates integration of effective cancer prevention, encouraging early detection, and utilization of resource adapted therapeutic and supportive interventions. Overly expensive drugs may consume resources; not just drugs for other conditions but paying for these may reduce the ability to invest in other cancer services like surgery, radiotherapy or early detection services. Access to cancer drugs is imperative but their price tag is creating a significant barrier to access.

Countries in the ME are heterogeneous in terms of income. However, they all have different aspects of challenge when it comes to implementing value based models. Many have other priorities such as improving quality and increasing access to basic health services. Others struggle with the challenges of fragmented systems, and the limits of existing healthcare infrastructure and operations. A particular challenge among others is the deficiency in the core components focusing on objective measures of outcomes and costs; including policies and institutions for value in healthcare. These obstacles are, indeed, shared by many other countries. As technology advances and new value-based approaches take hold in wealthy economies, those countries that are still investing in developing their health systems have an opportunity to learn from their experience, saving precious resources and delivering better long-term care for their societies.

Citation Format: Al Sukhun S. The challenge of definition and adoption; perspective from the Middle East [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 IS-2.
Abstract OT1-03-08: A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab and pertuzumab in HR-positive, Her2-positive metastatic breast cancer
Authors: Cascetta KP , Poulikakos P , Shapiro C , Fasano J , Bhardwaj A , Irie H , Goel A , Klein P , Adams S , Kalinsky K , Vahdat L , Ru M , Tiersten A
Published: February 2018

Background: Overexpression or amplification of HER2 occurs in approximately 15 – 20% of patients and about half of these tumors are hormone receptor (HR) positive. Studies suggest that this 10% of all breast cancer cases may derive less benefit from endocrine therapy than those with HR positive disease without HER2 overexpression. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. To date, no studies have examined the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in this patient population.

Trial Design: Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, Her2-positive Metastatic Breast Cancer.

Eligibility Criteria: Stage IV hormone receptor positive, HER2 positive breast cancer patients.

Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including cyclin D1 expression levels, phosphorylated retinoblastoma expression and p16 levels. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to see if there is correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.

Statistical Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. If ≥ 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or, if the highest level has been reached and < 33% of patients have experienced DLT, that will be considered the MTD. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients.

Accrual: Maximum of 36 subjects.

Citation Format: Cascetta KP, Poulikakos P, Shapiro C, Fasano J, Bhardwaj A, Irie H, Goel A, Klein P, Adams S, Kalinsky K, Vahdat L, Ru M, Tiersten A. A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab and pertuzumab in HR-positive, Her2-positive 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 OT1-03-08.
Abstract OT1-04-02: Mifepristone treatment for breast cancer patients expressing levels of progesterone receptor isoform A (PRA) higher than those of isoform B (PRB)
Authors: Liguori M , Lanari C , Gass H , Rojas P , Elia A , Martinez Vazquez P , Burruchaga J , Gonzalez P , Caillet Bois I , Ventura C , San Martin G , Castets A , Lovisi S , Acosta Haab G , Lamb C , Fabris V , Novaro V , Molinolo A
Published: February 2018

Seventy percent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to antiestrogen therapies. Emerging evidence from experimental studies and human epidemiology, points to a relevant role for progestins in breast carcinogenesis and cancer growth. Others and we have proposed that there is a role for antiprogestins in the therapeutic armamentarium, but the challenge remains to identify which patients would benefit from targeting the PR in addition to ER. Preclinical data indicates that antiprogestins block cell proliferation and increase apoptosis only in ER+ breast cancers expressing levels of PRA higher than those of PRB. The aim of this study is to evaluate the therapeutic effects of Mifepristone (MFP) on breast cancer patients selected by their PRA/PRB isoform ratio, for 14 days in between core biopsy and surgery (MIPRA trial ClinicalTrials.gov Identifier: NCT02651844). Methods: This is an open label, interventional with single group assignment study. We perform core biopsies on menopausal patients with clinically palpable breast cancers larger than 1.5 cm to confirm diagnosis. We will assess the PRA/PRB ratio by western blotting in frozen samples and total PR in formalin-fixed samples by immunohistochemistry (IHC). Twenty eligible PR+ patients (PR > 50 %) with PRA/PRB ≥1.5 who have signed consent forms, and meet the inclusion criteria will be recruited. Patients will be treated for 14 days with MFP p.o 200 mg. Surgery will be performed on day 15. Samples will be frozen for molecular studies or fixed for IHC. The primary outcome is the evaluation of Ki-67 staining pre- and post treatment. Secondary outcomes include comparatively expression of proliferation/apoptosis/PR signaling markers in core and surgical biopsy samples. Other pre-specified outcomes include molecular profiling, study of liquid biopsies, mammography, and ultrasound studies. Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient.

Citation Format: Liguori M, Lanari C, Gass H, Rojas P, Elia A, Martinez Vazquez P, Burruchaga J, Gonzalez P, Caillet Bois I, Ventura C, San Martin G, Castets A, Lovisi S, Acosta Haab G, Lamb C, Fabris V, Novaro V, Molinolo A. Mifepristone treatment for breast cancer patients expressing levels of progesterone receptor isoform A (PRA) higher than those of isoform B (PRB) [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 OT1-04-02.
Abstract OT1-05-01: A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer
Authors: Santa-Maria CA , Rampurwala M , Wisinski K , Toppmeyer D , O'Regan R
Published: February 2018

Background: Triple negative breast cancer (TNBC) is a heterogeneous disease encompassing distinct intrinsic molecular subtypes, including a luminal androgen receptor (AR) subtype, characteristically dependent on AR signaling. The AR is expressed in more than 50% of TNBCs. Bicalutamide is an oral, non-steroidal, AR antagonist, which has been studied in metastatic TNBC with a clinical benefit rate of 19% at 24 weeks. In preclinical models, cyclin dependant kinase (CDK) 4/6 inhibition has been shown to restore sensitivity to AR inhibition, and may thus be an important resistance mechanism. Ribociclib is an orally bioavailable, highly specific CDK4/6 inhibitor that induces cell cycle arrest, already approved in endocrine receptor positive breast cancers. We hypothesize that inhibition of CDK inhibition can enhance the activity of anti-androgen therapy in TNBC that express AR.

Methods: We designed a phase I/II, single arm, non-randomized, open label study of the combination of bicalutamide with ribociclib in women with advanced AR-positive TNBC. The primary objective of the phase I component is to determine the maximum tolerated dose of the combination, and of the phase II component to assess the clinical benefit rate at 16 weeks. Secondary objectives include progression free and overall survival, objective response rates, and safety and tolerability. Exploratory objectives will be to assess AR quantification, localization and splice variants in circulating tumor cells, as well as quantification of pan and phospho proteins of Rb. Eligible patients must have measurable metastatic or unresectable AR-positive TNBC and have had no more than 1 line of systemic therapy for metastatic disease. The phase I study will be conducted using a 3+3 dose escalation schema, 12 to 18 patients are expected to enroll. The phase II component will utilize a Simon's two stage design, enrolling 24 patients for the first stage. At least 5 subjects must have clinical benefit by 16 weeks to proceed onto the second stage, which would enroll an additional 22 subjects for a total of 46 patients. The study will be powered to detect a clinical benefit rate of 40% with a power of 80% and a type I error rate of 10%. Contact dmusapatika@hoosiercancer.org for more information about the study.

Citation Format: Santa-Maria CA, Rampurwala M, Wisinski K, Toppmeyer D, O'Regan R. A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ 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 OT1-05-01.
Abstract P1-01-11: Not presented
Authors: Wang Z , Humphries B , Li Y , Yang C
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-01-17: Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer
Authors: Liao N , Zhang G-C , Wang Y , Cao L , Li K , Ren C-Y , Wen L-Z , Shi Y , Zhu W , Chen X
Published: February 2018

Emerging evidence has revealed that the mutations in estrogen receptor alpha (ERα) gene (ESR1) is frequently observed in ER+ metastatic breast cancer, and is associated with the aggressively invasive and metastatic phenotype in advanced breast cancer due to the resistance of endocrine therapy. In our previous study, we have identified three novel mutations of ESR1, including ESR1 G74R, D230H and M250T, in the untreated patients with early breast cancer. However, the functional roles for these novel mutations in the cellular biology of breast cancer remain to be elucidated. In this study, we described the molecular mechanism underlying potential roles for the novel mutation ESR1 p.Met250Thr (c.749T>C) in regulating the cellular invasiveness of breast cancer. Firstly, we found, as compared with wild-type (WT) HA-ESR1, forced expression of HA-ESR1 M250T enhanced the invasive capacity of breast cancer MCF-7 cells by using Transwell assay. Moreover, we found that the levels of miR-190 were significantly up-regulated in the MCF-7 (HA-ESR1 M250T) cells, and further verified that miR-190 played an important role in ESR1 M250T-mediated induction of cellular invasiveness by using specific shRNA to knock down miR-190 levels in MCF-7 (HA-ESR1 M250T) cells. Further bioinformatics analysis showed that there were several half Estrogen Response Elements (EREs) in the promoter region of Talin-2, as the host gene of miR-190. Talin-2-driven luciferase reporter assay indicated ESR1 M250T resulted in a higher increase in the luciferase activity than ESR1 WT. Chromatin-immunoprecipitation (ChIP) assay identified a higher binding ability with Talin-2 promoter for ESR1 M250T than ESR1 WT. Collectively, our mechanistic study revealed that the ESR1 M250T mutation, located in the DNA-binding domain, increased the invasive capacity of breast cancer cells via the transcriptional induction of Talin-2 and miR-190. The potential role for ESR1 M250T in affecting the efficacy of endocrine therapy has been under the investigation in our laboratory, and the result from which will help us better elucidate the clinical relevance for novel ESR1 mutations in affecting the sensitivity of endocrine therapy.

This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768).

Citation Format: Liao N, Zhang G-C, Wang Y, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of 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 P1-01-17.
Abstract P1-02-05: The effect of obesity and metabolic factors on genomic assays for risk of recurrence
Authors: Soliman H , Treece T , Audeh W ,   IMPACt Investigators Group I
Published: February 2018

Background: Obesity and other factors contributing to metabolic syndrome (MS) have become increasingly prolific in today's population. They are also known risk factors or comorbidities in many disease states including breast cancer (BC). While obesity and MS are known to increase the risk of developing BC, the effect on the risk of distant recurrence is uncertain. This substudy evaluated the relationship of BMI, blood pressure, cholesterol, triglyceride, diabetic status, and MS on the risk of recurrence in early BC patients. Methods: The effect of these metabolic factors on MammaPrint (MP) and Oncotype DX (ODX) risk of recurrence assays was compared. Additionally, gene expression analysis was performed to elucidate the differences between obese patients who were MP high risk (HR) vs. low risk (LR), and MP HR patients who were obese vs. not-obese. This subanalysis included patients from the PROMIS (n=198) and IMPACt (n=382) studies for whom metabolic characteristics were captured with informed consent. From the IMPACt study, 98 patients also reported ODX results (RS range 0-69). Results: By BMI, 1% of patients were classified as underweight (BMI <18.5), 22% normal (18.5≤ BMI <25), 31% overweight (25≤ BMI <30), and 46% as obese (BMI ≥30). To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors. In the full cohort, having MS was significantly associated with ethnicity (p < 0.05) and menopausal status (p < 0.001), but not histopathological tumor type, histological grade, tumor stage, or lymph node status (p > 0.05). 36% (207/580) of patients were considered as having MS in the full cohort, similarly 36% (35/98) had MS in the ODX subset. Of the patients with MS, MP classified 52% (108/207) as HR. For the subset of ER-positive patients with an ODX result, ODX classified the 11% (4/35) as HR whereas MP classified 57% (20/35) of the same patients as HR. Conclusions: Patients with obesity as measured by BMI and with MS were more frequently classified as HR by MP, in contrast to ODX which classified nearly all patients as intermediate or LR, confirming previous findings by Robinson, et. al (SABCS 2012 and 2014). Understanding the biological foundation of how obesity and metabolic factors affect risk of recurrence in breast cancer will improve both the treatment and care of patients.

Citation Format: Soliman H, Treece T, Audeh W, IMPACt Investigators Group I. The effect of obesity and metabolic factors on genomic assays for risk of recurrence [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 P1-02-05.
Abstract P1-03-05: Not presented
Authors: Slavik J , Wang S , Tao L , Shukla A , Clancy R , Ellsworth R , Smith RD , Rodland KD , Cutler ML , Shriver CD , Iida J
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-03-10: Breast tumour kinase and its role in mTOR signalling
Authors: Harvey A , Foster H , Thorpe M , Karteris E
Published: February 2018

Background: The development of distal metastases and the acquisition of resistance to chemotherapeutic agents are one of the leading causes of cancer related death in breast cancer patients. There is both a scientific and clinical need to understand the alterations in cellular signalling pathways that could contribute to chemotherapeutic resistance in breast cancer, thereby identifying novel targets for therapy. The intracellular tyrosine kinase Brk/PTK6 enhances coupling of ErbB signalling to PI3K/Akt and we hypothesise that Brk plays a role in chemo-resistance and activation of downstream effectors such as mTOR.

Methods: The protein and activation levels of mTOR pathway components and expression levels of Brk, in both Taxol-sensitive and resistant breast cancer cells, were examined by western blotting and immunofluorescence. Brk transfected cells were treated with BEZ-235 for 72 hours and relative cell numbers determine by MTT assay. Immunoprecipitation studies were carried out on lysates from T47D cells, transfected to express FLAG-tagged Brk, with ANTI-FLAGM2 agarose beads. Sequence alignment was done using the NCBI BLAST Tool.

Results: We found that mTOR signalling was up-regulated in the Taxol-resistant cell line compared to parental Taxol-sensitive cells. This up-regulation was also accompanied by increased Brk levels. Transfection of a Brk-negative breast cancer cell line, MDA-MB-468 with wild-type Brk resulted in increased levels of both mTOR and, to a lesser extent, the downstream signalling component GβL at the protein level compared to cells transfected with vector only. Levels of the mTOR inhibitor DEPTOR were also decreased in response to Brk expression and mTOR co-precipitated in FLAG-Brk pull downs using FLAG M2 beads.

The Taxol resistant cells also showed altered responses to the mTOR inhibitor RAD-001/everolimus. Interestingly, sequence alignment revealed that there are common amino acid motifs between Brk and the mTOR regulatory molecule DEPTOR.

Conclusions: These data implicate Brk in up-regulating mTOR expression and indicate that Brk may influence mTOR signalling in the development of Taxol resistance. It is possible that Brk could substitute for DEPTOR in mTOR complexes providing a mechanism for elevated mTOR signalling in many breast cancers.

Citation Format: Harvey A, Foster H, Thorpe M, Karteris E. Breast tumour kinase and its role in mTOR signalling [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 P1-03-10.
Abstract P1-04-01: A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy in human breast cancer
Authors: Cheng L , Wang J , Liu R
Published: February 2018

Background: Oncolytic herpes simplex virus-1 (oHSV-1) vectors are promising new therapeutic agents for cancer. For the nuerovirulence of ICP34.5 protein, the encoding gene named γ34.5 is deleted in all oHSV-1 mutants currently in clinical trials. However, the deletion of γ34.5 also promotes the interferon-induced shutoff of virual protein synthesis, and attenuates the virus replication in cancer cells at the same time. Previous studies reported that the carboxyl-terminus of MyD116/GADD34 was homologous to that of γ34.5 gene; hence, it might substitute for γ34.5 gene to enhance the replication and cytotoxicity of the virus. Objective: To reconstruct a novel oHSV-1 mutant named GD116 by inserting γ34.5-MyD116 chimeric gene into G47Δ genome, and to investigate whether the carboxyl-terminus of murine MyD116 can enhance the antitumour efficacy of GD116 on human breast cancer cell line in vitro and in vivo. Methods: Using G47Δ genome and bacterial artificial chromesome (BAC) as the backbone, the GD116 virus expressing γ34.5-MyD116 was reconstructed via Cre/loxp and FLP/FRT recombinase systems. A GD-empty virus mutant containing only the CMV sequence was also constructed as a control at the same time. Then, the replication and cytotoxicity of these two virus mutants in MDA-MB-231 humanbreast cancer cell line was evaluated in vitro. Meanwhile, the subcutaneous tumor model was also generated by injecting MDA-MB-231 cells into the right flank of BALB/c mice. Then, the antitumor efficacy of GD116 on breast cancer in vivo was evaluated by intratumoral injection. Results: Compared with GD-empty, GD116 possessed an enhanced replication capability and oncolytic efficacy in MDA-MB-231 cell line. On the fifth day after infection with GD116 at MOIs of 0.1 and 0.3, 35.0% and 50.2% of MDA-MB-231 cells were killed respectively, which were higher than that with GD-empty (24.3% and 37.8%). Additionally, GD116 exhibited enhanced antitumor efficacy on subcutaneous tumor xenografts of human breast cancer cells in vivo compared with GD-empty. On day 21 after treatment, the average tumor volume of mice was 585.5 mm3, 289.0 mm3 and 121.9 mm3 in Control, GD-empty and GD116 group respectively. Conclusion: Our findings indicate that the carboxyl-terminus of the murine MyD116 can substitute for the corresponding domain of the γ34.5 gene in oHSV-1 to promote the replication of the virus in infected cancer cells; and the mutant GD116 armed with γ34.5-MyD116 chimaera has enhanced oncolytic effect on MDA-MB-231 breast cancer cells in vitro and in vivo.

Citation Format: Cheng L, Wang J, Liu R. A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy 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 P1-04-01.
Abstract P1-07-35: Adipokine receptor CAP1 expression as predictor of survival outcome among breast cancer patients
Authors: Rosendahl AH , Bergqvist M , Kimbung S , Borgquist S
Published: February 2018

Background: Obesity is a challenging health concern in breast cancer. Not only are obese women at higher risk of breast cancer, but if diagnosed with the disease, obesity is also impairing the prognosis of a breast cancer. Understanding the underlying biology behind these associations are key to improve survival rates in breast cancer. In obesity, the more abundant, activated adipose tissue may lead to insulin resistance and secretion of soluble mediators that may contribute to impaired breast cancer outcomes observed among obese women. The adipokine resistin is implied to be an important link between obesity and insulin resistance, and to be elevated among breast cancer patients. Yet, the expression of the newly identified resistin receptor CAP1 and its impact on breast cancer prognosis is poorly understood.

Purpose: To evaluate the impact by the adipokine receptor CAP1 tumor expression on breast cancer outcomes.

Experimental Design: CAP1 mRNA expression was explored among 1,881 primary breast tumors. Associations between CAP1 expression, categorized into tertiles, and survival outcomes were estimated using the Kaplan-Meier method and log-rank test, and by multivariable Cox regression models providing adjusted hazard ratios (HRadj) with 95% confidence intervals (CI). Independent biological network interaction analyzes were conducted in a subset of 1,105 invasive breast carcinomas within The Cancer Genome Atlas (TCGA) project.

Results: CAP1 was linked to poor tumor characteristics with higher CAP1 expression found among estrogen receptor (ER)-negative tumors, relative to ER-positive tumors, as well as with increasing tumor grade (P=0.025). High CAP1 tumor expression was further associated with shorter overall survival (HRadj 1.54; 95% CI, 1.11-2.13) and relapse-free survival (HRadj 1.47; 95% CI, 1.10-1.96), compared with low or intermediate CAP1 expression, particularly among ER-positive tumors or lymph node positive tumors. Additionally, CAP1 was identified in complex with genes involved in growth promoting and cell motility processes.

Conclusion: These results highlight the potential role of the resistin receptor CAP1 regarding breast cancer outcomes. Further investigations are needed to elucidate the biological and clinical implication of the resistin-CAP1 link in obesity-associated breast cancer.

Citation Format: Rosendahl AH, Bergqvist M, Kimbung S, Borgquist S. Adipokine receptor CAP1 expression as predictor of survival outcome among breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-35.
Abstract P1-08-04: Not presented
Authors: Somlo G , Yuan Y , Waisman J , Yeon C , Frankel P , Hou W , Hurria A , Tank N , Sedrak M , Synold T , Mortimer J , Lee P
Published: February 2018

This abstract was not presented at the symposium.
Abstract P1-08-05: A phase I trial of chemotherapy followed by infusions of activated T cells armed with anti-CD3 and anti-HER2 bispecific antibody for stage III, Her2+ or Her2- breast cancer
Authors: Dillon P , Rathore R , Thakur A , Colvin G , Kouttab N , Lum L
Published: February 2018

Background: The balance in the immune system between immune surveillance and tolerance is known to be associated with the prognosis of breast cancer patients. The aim of this phase I study was to assess the safety of anti-CD3 x anti-HER2Bi bispecific antibody targeted (BAT) activated T cells (TC) in high risk breast cancer patients. The BAT T-cells exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement.

Methods: High risk adjuvant breast cancer patients were recruited and completed standard adjuvant chemotherapy. BATs were produced by stimulating peripheral blood mononuclear cells (PBMC) obtained by leukapheresis; collected TC were then activated with anti-CD3 monoclonal antibody and expanded in IL-2 for 12-14 days. TC were armed with bispecific antibody and cryopreserved until used. Groups of 3 patients received 20, 40, 80 or 160 x 109 BATs per infusion twice a week for four weeks. All patients were treated at Roger Williams Medical Center.

Results: Nine patients were accrued and all had N3 disease. Eight of 9 patients were ER positive; 2 of 9 were HER2 overexpressing. The median OS has not reached as five of nine patients are still alive. OS range from 14.3 to 154.7 months (as December 11, 2016). Five out of the five patients who are alive have no evidence of disease and 1 patient had a secondary primary that has been successfully treated and she has no evidence of disease. It was feasible to grow up to 160 x 109 BATs and this dose level was tolerable without any cell-based dose limiting toxicities. BATs persisted in the blood for at least a week. BAT infusions induce cellular anti-tumor responses and cytokine responses.

Conclusion: Targeting HER2 positive and negative tumors induced cytotoxic anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels. The prolonged survival in a high risk population suggests that BAT infusions provided a clinical benefit. These results are being confirmed in a phase II trial for metastatic breast cancer.

Citation Format: Dillon P, Rathore R, Thakur A, Colvin G, Kouttab N, Lum L. A phase I trial of chemotherapy followed by infusions of activated T cells armed with anti-CD3 and anti-HER2 bispecific antibody for stage III, Her2+ or Her2- breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-08-05.
Abstract P1-09-01: A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC)
Authors: Rugo HS , Kabos P , Dickler MN , John WJ , Smith I , Lu Y , Young S , Tolaney SM
Published: February 2018

Background: Abemaciclib is a selective and potent small molecule inhibitor of CDK4 and 6, with evidence of single-agent antitumor activity, and a safety profile that enables dosing on a continuous schedule. Abemaciclib demonstrated anti-tumor activity as a single agent with a 19.7% objective response rate for women with previously treated HR+, HER2- MBC1. In the phase 1b study JPBH, abemaciclib demonstrated a tolerable safety profile when combined with endocrine or HER2 targeted agents for MBC2. Abemaciclib given BID in combination with pembrolizumab also demonstrated a tolerable safety profile in phase 1b study of stage IV NSCLC3.

Methods: JPCE is a multicenter, nonrandomized, open-label, phase 1b study of abemaciclib plus pembrolizumab for patients with HR+, HER2- MBC or NSCLC (ClinicalTrials.gov NCT02779751). The study has 3 disease-specific cohorts, each with approximately 25 patients (N=75); the HR+, HER2- MBC cohort (part C) will be presented here. The primary objective was to characterize safety of the abemaciclib and pembrolizumab combination. Secondary objectives included efficacy endpoints (objective response rate, disease control rate, duration of response, progression-free survival, and overall survival), pharmacokinetics of abemaciclib plus pembrolizumab, and changes in patient-reported pain and disease-related symptoms. Patients received 150 mg of abemaciclib orally Q12H plus pembrolizumab 200 mg as a 30-minute IV infusion on Day 1 every 21 days. Eligible patients included women with confirmed HR+, HER2- MBC who have previously received at least 1 but no more than 2 prior chemotherapy regimens for MBC; are able to provide tumor tissue at baseline and at cycle 3, day 1; have measurable disease (RECIST v.1.1), adequate organ function, ECOG PS ≤1, are able to swallow oral medications; and have not received treatment with CDK4 & 6 or PD-1/ PD-L1 inhibitors.

Results: At the time of abstract submission, study JPCE part C cohort (HR+, HER2- MBC) was fully enrolled at 25 patients. Data to be presented include patient demographics, baseline disease characteristics, adverse events by frequency and by grade, and preliminary efficacy of the abemaciclib plus pembrolizumab combination in HR+, HER2- MBC.

References:

1. Dickler et al, Clin Cancer Res. 2017

2. Goetz et al. poster presented at SABCS, 2015

3. Goldman et al. poster presented at IASLC 2016

Citation Format: Rugo HS, Kabos P, Dickler MN, John WJ, Smith I, Lu Y, Young S, Tolaney SM. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) [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 P1-09-01.