bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract I18: Retooling a blood-based biomarker into a theranostic agent
Authors: Lewis Jason S.
Published: March 2020

Over the past 30 years, our ability to noninvasively diagnose, localize, and treat many forms of cancer has grown significantly. However, the biomolecular basis of many malignancies—most notably pancreatic cancer—remains convoluted, and technical advances have not translated to significantly improved survival rates. This is reflected in 1- and 5-year survival rates of 27% and 6%, respectively, for pancreatic cancer diagnoses. Given the tremendous current focus on the creation of new therapeutics for treating pancreatic cancer, the development of companion technologies that can safely, accurately, and unambiguously aid in the early diagnosis, staging, and treatment monitoring of pancreatic cancer is a vitally important—yet unmet—clinical need. The remarkable specificity and selectivity of antibodies for cancer biomarkers have made immunoglobulins some of the most flexible and adaptable tools in modern medicine. For therapeutic purposes, a wide range of nonlabeled antibodies has now entered the clinic. Antibody-based PET and SPECT imaging agents are not far behind. For example, an array of 89Zr-labeled radioimmunoconjugates has shown significant promise in both preclinical and clinical studies. CA19-9 levels in the serum are routinely used for diagnosis, risk stratification, and follow-up of PDAC. While CA19-9 is a shed antigen entering the circulation, the concentration is much higher in the tumor tissue, making it a potential target for in vivo imaging with radiolabeled antibodies. Our studies show that a tumor antigen secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. For example, in proof-of-concept preclinical studies, we were able to visualize pancreatic cancer xenograft and orthotopic models of early- and late-stage disease with excellent tumoral uptake and target-to-non-target ratios using the 89Zr-labeled human monoclonal antibody [89Zr]Zr-DFO-HuMab-5B1 (MVT-2163, NCT02687230). This 5B1 radioimmunoconjugate scaffold has also been deployed with therapeutic beta- and alpha-emitting radionuclides, creating an effective radiotherapeutic paradigm for the imaging and therapy of PDAC. In conclusion, our study shows that a tumor antigen secreted by PDAC to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and provides new opportunities for noninvasive characterization of tumors in pancreatic cancer patients.

Citation Format: Jason S. Lewis. Retooling a blood-based biomarker into a theranostic agent [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I18.
Abstract I22: New players and unique features of cancer lysosomes
Authors: Perera Rushika M
Published: March 2020

Pancreatic ductal adenocarcinoma (PDA) cells and tumors constitutively activate nutrient scavenging pathways, namely, autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material) in order to maintain metabolic homeostasis. Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Our prior work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. PDA tumors are effectively “addicted” to enhanced catabolic activity as blocking lysosome function specifically inhibits in vitro and in vivo growth of PDA cell lines and tumor xenografts with minimal effects on normal cells. How key changes in lysosome composition and content contribute to the aggressive nature of PDA remains an open question. We have optimized methodologies to isolate and purify lysosomes from normal human pancreatic epithelial cells and several established patient-derived PDA cancer cell lines, using affinity-based capture techniques that isolate 50-80% intact lysosomes free of cytoplasm and other contaminating organelles. By systematically implementing lysosome purification from normal, primary, and metastatic PDA tumors combined with mass spectrometry-based proteomics, we have identified both resident and substrate proteins that are uniquely associated with PDA lysosomes. Several cancer-specific lysosomal membrane proteins emerged from this analysis that may endow cancer lysosomes with enhanced functionality, including rapid membrane repair in the face of sustained mechanical and chemical insults. Similarly, we find that PDA lysosomes degrade select cellular proteins to enable dynamic remodeling of the cellular proteome in a manner that favors tumor growth and progression. Collectively, our data provide strong evidence in support of the lysosome as a central mediator of cellular adaptation to stress and promoter of tumorigenesis.

Citation Format: Rushika M Perera. New players and unique features of cancer lysosomes [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I22.
Abstract I25: Understanding and exploiting natural barriers to pancreatic tumorigenesis
Authors: Lowe Scott W.
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily aggressive cancer that arises in the context of a unique tumor microenvironment. Molecularly, PDAC involves a combination of undruggable cancer drivers, including activating mutations in the KRAS oncogene and disruption of tumor suppressors such a TP53, SMAD4, and CDKN2A together with poorly characterized epigenetic changes that correlate with metastatic progression. Histologically, PDAC arises within a heterogeneous tissue microenviroment characterized by dense fibroinflammatory stroma that influences disease progression and limits therapy response. Our laboratory has developed genetically engineered mouse models based on ES cells (GEMMESCs) of pancreas cancer, where chimeric mice are produced directly from multiallelic ES cells harboring a latent KrasG12D oncogene together with all the genetic elements needed for Kras activation in the together with those needed for tetracycline-inducible (and reversible) regulation of short hairpin RNAs targeting capable of suppressing any gene of interest at any time after pancreas cancer initiation. Using this system, we have probed the epigenetic requirements for pancreas cancer initiation and compare them to those required for pancreatic regeneration following tissue damage; in addition, we have explored the metabolic programs needed for p53 to suppress tumorigenesis. Our studies have identified elements of cellular plasticity that act at multiple points that suppress pancreas cancer progression and identify actionable intervention points required for these transitions.

Citation Format: Scott W. Lowe. Understanding and exploiting natural barriers to pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I25.
Abstract PR05: Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules
Authors: Yamamoto Keisuke , Venida Anthony , Biancur Doug E. , Yamamoto-Kakiuchi Miwako , Sohn Albert P. , Perera Rushika M. , Kimmelman Alec C
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy refractory to most therapies, including immune checkpoint blockade (ICB). Autophagy is a highly conserved self-degradation process that recycles cellular components. PDAC requires high levels of autophagy/lysosome function to meet their metabolic demand under nutrient-deprived conditions; however, little is known about substrates that are preferentially targeted and subsequent biologic impacts of their loss on PDAC pathogenesis. Here we found that cell surface expression of major histocompatibility complex class I (MHC-I) molecules, a critical component of antigen-presentation to CD8+ cytotoxic T lymphocytes (CTLs), is downregulated in PDAC cells though an autophagy-dependent pathway. Autophagy inhibition in PDAC cells restored surface MHC-I levels and improved antigen presentation, leading to enhanced antitumor T-cell response in syngeneic mouse models of PDAC, which was further enhanced by combination with ICB. Our findings indicate that elevated autophagy/lysosome function facilitates immune evasion of PDAC cells through selective targeting of MHC-I molecules and provide a rationale for the combination of autophagy inhibition and ICB as a therapeutic strategy against PDAC.

This abstract is also being presented as Poster B61.

Citation Format: Keisuke Yamamoto, Anthony Venida, Doug E. Biancur, Miwako Yamamoto-Kakiuchi, Albert P. Sohn, Rushika M. Perera, Alec C Kimmelman. Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR05.
Abstract PR10: Enhancing the effect of autophagy inhibition for pancreatic cancer treatment
Authors: Bryant Kirsten L. , Klomp Jennifer E. , Lee Ye S. , Stalnecker Clint A. , Grover Kajal R. , Edwards A. Cole , Peng Sen , Pierobon Mariaelena , Petricoin Emanuel F. , Tran Nhan , Kimmelman Alec C. , Cox Adrienne D. , Der Channing J.
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression, which blocks proliferation, was associated with increased rather than decreased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and also increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. Addressing a mechanism for ERK suppression-increased autophagy, we describe three mechanisms: 1) ERK inhibition-mediated increased transcription of autophagy and lysosomal genes, 2) ERK inhibitor-induced AMPK activation and suppression of mTOR signaling, and 3) ERK inhibition-facilitated decreased glycolytic flux. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated antiproliferative activity. Similarly, genetic or pharmacologic inhibition of specific regulators of autophagy also enhanced ERK inhibitor activity. Encouraged by the synergistic relationship between ERK and autophagy inhibition, we performed a CRISPR/Cas-9 mediated genetic loss of function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple mediators of the DNA damage response. One such sensitizing gene was CHEK1, which encodes the CHK1 serine/threonine kinase, required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to DNA damage. Accordingly, we showed that treatment with prexasertib, a clinical candidate CHK1 inhibitor, increased autophagic flux in PDAC cells and synergized with CQ to decrease PDAC cell proliferation and increase apoptosis. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment.

This abstract is also being presented as Poster B07.

Citation Format: Kirsten L. Bryant, Jennifer E. Klomp, Ye S. Lee, Clint A. Stalnecker, Kajal R. Grover, A. Cole Edwards, Sen Peng, Mariaelena Pierobon, Emanuel F. Petricoin III, Nhan Tran, Alec C. Kimmelman, Adrienne D. Cox, Channing J. Der. Enhancing the effect of autophagy inhibition for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR10.
Abstract ES10-1: Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells
Authors: Blanpain C
Published: March 2020

Stem cells ensure tissue development, homeostasis and repair. We have recently developed new methods to study by lineage tracing the cellular hierarchy and clonal dynamics that govern the development and homeostasis of the mammary gland. I will present new studies combining lineage tracing, clonal analysis, lineage ablation, single cell RNA sequencing, chromatin profiling, and functional experiments in vivo to investigate the cellular and molecular mechanisms regulating multipotency and lineage restriction during mammary gland development and the cellular reprograming occurring after oncogene expression. Defining the mechanisms regulating tissue expansion and cell fate during development and adult regeneration and understanding how these mechanisms are corrupted during tumorigenesis will have important implications for regenerative medicine and cancer therapy.

This work is supported by the ERC, WELBIO, FNRS, TELEVIE, and the Fondation Baillet-Latour.

Citation Format: C Blanpain. Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES10-1.
Abstract ES12-2: Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer
Authors: Helleday T
Published: March 2020

DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Our strategy is to exploit endogenous DNA damage caused by cancer vulnerabilities, by DNA repair inhibitors using a synthetic lethal strategy. Our early work on PARP inhibitors in BRCA mutated cancers is establishing in breast cancer and here I will describe novel DNA repair targets and how these can be integrated into treatment of breast cancer. Here, I will also describe a novel link between PARP and hormone dependent cancers. Interestingly, we show that the PARP related protein NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation and a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. The NUDT5 protein is critical for 3D organoid growth of breast cancer cells. Here, we confirm the involvement of NUDT5 in ADP-ribose metabolism and identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can effectively block growth of 3D breast cancer organoids.

Citation Format: T Helleday. Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-2.
Abstract ES4-2: Single cell transcriptomics reveals multi-step adaptations to endocrine therapy
Authors: Magnani L , Barozzi I , Hong S
Published: March 2020

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. During this talk, I will briefly introduce a series of molecular tools that can be used to study transcriptional changes at the single cell level in relevant models. I will then show how used these tools to dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we could disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. I will then update the audience on how it is possible to integrate these technologies directly into clinical studies and what developments are happening in the field of single cell technologies. I will finally propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

Citation Format: L Magnani, I Barozzi, S Hong. Single cell transcriptomics reveals multi-step adaptations to endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES4-2.
Abstract ES5-3: Surgical considerations after preoperative therapy for hormone receptor positive breast cancer
Authors: King TA
Published: March 2020

Session Title: Multidisciplinary approaches to optimize surgical therapy in hormone receptor positive breast cancer

Talk Title: Surgical considerations after preoperative therapy in hormone receptor positive breast cancer

Abstract:

Preoperative therapy increases rates of breast conservation and decreases the need for axillary lymph node dissection (ALND) in select patients. In hormone receptor positive (HR+) HER2 negative breast cancer patients the choice between neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET) to achieve breast conservation can be challenging and the low rates of axillary pCR with either approach have been associated with higher rates of ALND. For HR+ HER2- patients receiving NAC, available literature supports performing sentinel lymph node biopsy (SLNB) after receipt of therapy with the decision to perform axillary lymph node dissection dictated by the status of the sentinel lymph nodes. For patients receiving NET, there is little data to guide surgical management of the axilla. In a recent review of the NCDB, we assessed axillary management by initial treatment strategy (NET, NAC, or upfront surgery) among a large population of Stage II-III HR+ HER2- breast cancer patients and found that SLNB use after NET in both clinically node negative and clinically node positive patients was similar to SLNB use with upfront surgery. However, among those with pN1 disease, patients who received NET were less likely to undergo ALND. While failure to achieve a nodal pCR after NAC is associated with inferior DFS and OS outcomes; whether or not the same is true after NET remains uncertain. Further, the impact of residual nodal disease after NET on LRR remains an area of ongoing investigation. Understanding the differences in and implications of residual nodal disease after neoadjuvant therapy (NAC vs NET) in HR+ HER2- breast cancer provides the opportunity to develop subtype specific strategies for optimal surgical management of the axilla.

Citation Format: TA King. Surgical considerations after preoperative therapy for hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES5-3.
Abstract ES8-3: Everything Comes at a Price - Toxicity, Cost and Adherence to Endocrine Therapy
Authors: Hershman DL
Published: March 2020

Despite the proven efficacy of aromatase inhibitors (AIs) for the treatment of hormone-sensitive breast cancer (BC) adherence to therapy for the full duration of 5-years is suboptimal. Adherence is likely even lower for extended adjuvant therapy for up to 10-years. Issues related to non-adherence are increasingly important, as analyses from prospective randomized trials show compliance to endocrine therapy is associated with improved disease-free survival. The reasons for non-adherence to hormonal therapy are multifactorial. Barriers to compliance include patient, physician, medication and system related variables and poor compliance is usually associated with a combination of these factors. Characteristics associated with non-adherence include very high and low age, minority race, being single, increased number of comorbidities, lack of knowledge about efficacy of AI therapy, history of non-adherence to other chronic medications, limited insurance status, and higher out of pocket costs.

Side effects from hormonal therapy is the most common reason for early discontinuation. AI arthralgia has been estimated to affect 45-60% of patients, many of whom report severe or continuous pain. One study reported an overall AI discontinuation rate of 32.4% within 2 years due to adverse effects, 24.3% specifically due to musculoskeletal symptoms, which was the primary reason for discontinuation. There is no consensus on the best treatment for AI arthralgia. The most commonly used therapy is NSAIDs, although there are no formal data testing their efficacy for AI arthralgia, and they are associated with potentially severe adverse effects. Randomized controlled trials have shown benefits from exercise (aerobic and strength training exercises), acupuncture, omega-3-fatty acids and duloxetine compared to placebo for AI arthralgia. Studies have also demonstrated improvement in symptoms over time even among patients receiving placebo. Various educational interventions have also been studied to improve adherence. A systematic review of behavioral interventions to enhance adherence to hormone therapy found five articles that met inclusion criteria and none reported the interventions significantly enhanced adherence compared to usual care. All evaluated educational interventions with or without reminders or navigation. In addition, a multicenter randomized clinical trial of patients with early stage breast cancer on AI’s found that bi-weekly unidirectional text messages for 36 months focused on overcoming potential barriers to medication adherence did not result in improved adherence to hormonal therapy. It is likely that improving long-term adherence will likely require sustained behavioral interventions and support.

Citation Format: DL Hershman. Everything Comes at a Price - Toxicity, Cost and Adherence to Endocrine Therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES8-3.
Abstract ML: What would Bill think?
Authors: Sparano JA
Published: March 2020

Since the untimely passing of Bill McGuire in 1992, breast cancer mortality rates have declined by approximately 40% despite stable incidence rates, largely due to mammographic screening and broader application of systemic adjuvant therapy in early stage disease. Continued progress is likely given recently reported clinical trials demonstrating improved survival in metastatic disease, including immune checkpoint blockade in triple negative disease, CDK4/6 inhibitors in ER-positive disease, and second-generation immunconjugates in HER2-positive disease. This remarkable progress in reducing breast cancer mortality has come with a price - broader use of adjuvant chemotherapy in patients with early stage disease who might have been adequately treated and perhaps cured without chemotherapy, and the short and long term side effects that may accompany it - which raises the question - what would Bill think of our progress? How would he challenge us to do better?This lecture will focus on three distinct topics that address some potential challenges: (1) How can gene expression profiles and other diagnostic tests be used to guide the use of adjuvant systemic therapy? (2) is time for reappraisal of active surveillance to detect impending recurrence and prevent it? (3) Are there diagnostic and therapeutic strategies that can be used to identify tumors at highest risk of systemic dissemination, and novel therapeutic strategies that block dissemination?

Citation Format: JA Sparano. What would Bill think? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ML.
Abstract MS2-2: Targeting the cell cycle - Beyond CDK4/6 inhibition
Authors: Jeselsohn R
Published: March 2020

Over the past several years three CDK4/6 inhibitors were approved for the treatment of metastatic ER+ breast cancer. This class of drug has had a major impact on patient outcomes and more recent analyses showed improvement in overall survival in addition to a significant delay in the need for chemotherapy and increase in progression free survival. Despite the remarkable clinical benefit, there are patients who have primary resistance to CDK4/6 inhibitors and the majority of patients will ultimately develop resistance to this class of drugs. Multiple pre-clinical studies and some clinical data have provided insights to the mechanisms of resistance to CDK4/6 inhibitors guiding the development of clinical trials after progression on a CDK4/6 inhibitor. In this presentation, I will review the mechanisms of resistance to CDK4/6 inhibitors and the ongoing clinical trials investigating novel therapeutic strategies to enhance responses to CDK4/6 inhibitors and for treatment after the acquisition of resistance to CDK4/6 inhibitors.

Citation Format: R Jeselsohn. Targeting the cell cycle - Beyond CDK4/6 inhibition [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS2-2.
Abstract OT1-01-06: A pilot study utilizing a HER2 directed dendritic cell vaccine during neoadjuvant therapy of HER2+ breast cancer
Authors: Soliman Hatem , Hogue Deanna , Han Hyo , Khong Hung , Costa Ricardo , Armaghani Avan , Muller Axia Soyano , Khakpour Nazanin , Lee Marie C , Kiluk John , Czerniecki Brian
Published: March 2020

Background: During the natural progression of early breast cancer, it has been demonstrated that the protective host immune response against HER2 is lost early on. Using a type 1 dendritic cell (DC1) vaccine loaded with HER2 peptides has been shown to be effective in restoring anti HER2 immune responsiveness and can lead to regression of very early non-invasive breast cancers. Prior investigations conducted by our group has suggested DC vaccines may sensitize cancers to subsequent systemic chemotherapy, and the Geparnuevo trial also suggested a prechemotherapy dosing with checkpoint therapy may improve pathologic complete response (pCR) rates in TNBC. We launched a pilot study to demonstrate safety, feasibility, and preliminary efficacy of administering the DC1 HER2 vaccine for 3 weeks prior to the initiation of neoadjuvant systemic therapy for stage II-III ER-HER2+ breast cancer. Methods: This single site study is a pilot design with a safety run in phase (n = 12) followed by an expansion cohort of 18 patients. Patients with stage II-III ER-HER2+ breast cancer who are eligible to receive neoadjuvant HER2 based chemotherapy (TCHP) can enroll. The safety run in evaluates two schedules of DC1 vaccination (ARM A = once weekly x 3 weeks and ARM B = twice weekly x 3 weeks) and will enroll six patients in each arm. After the first 3 weeks of DC1 neoadjuvant chemotherapy will be administered using standard docetaxel, carboplatin, trastuzumab, and pertuzumab given intravenously once every 3 weeks for 6 cycles. Booster vaccines will be given at weeks 25, 56, 80, and 104 and immune monitoring will be performed at these timepoints. The safety run in will evaluate safety using CTCAE 4.03 criteria along with the immunogenicity of each arm measured by ELISPOT. The arm with the best immune response at 3 weeks will be selected to proceed forward during the expansion cohort using an endpoint of pCR. Secondary endpoints will be recurrence free survival rate at 3 years and immune response. The pilot design is hypothesis generating but is likely able to detect a significant difference in pCR if the true rate is 75% assuming a historical rate of 55%. Accrual to the safety run in phase is complete and the expansion phase is underway using the twice weekly vaccination schedule.

Citation Format: Hatem Soliman, Deanna Hogue, Hyo Han, Hung Khong, Ricardo Costa, Avan Armaghani, Axia Soyano Muller, Nazanin Khakpour, Marie C Lee, John Kiluk, Brian Czerniecki. A pilot study utilizing a HER2 directed dendritic cell vaccine during neoadjuvant therapy of HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-06.
Abstract OT2-01-05: A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer
Authors: Alves Leandro , Gagliato Débora , de Paula Mayara , Cardoso Ana Carolina , Alcantara Alexandre , Precivale Maristela , Castilho Vivienne
Published: March 2020

Background: Treatment with anti-HER2 therapy significantly improved survival outcomes in patients with HER2-positive Breast Cancer (BC). In Brazil, Trastuzumab was the first biosimilar approved in the treatment of patients with breast (any disease setting) and advanced gastric cancer with overexpression of HER2. Increase access to this important treatment may be enhanced with biosimilar approval. The aim of this Real-World study is to assess the efficacy and safety of adjuvant biosimilar trastuzumab in Brazilian patients with early HER2+ BC. Methods: This is a national, multicenter, observational prospective, real-world study in a variety of Brazilian institutions. A hundred and seventy adult patients, with diagnosis of early stage HER2-positive breast cancer, who received at least one dose of biosimilar trastuzumab (Zedora) as adjuvant therapy will be included. Patients will be followed for 5 years after the use of biosimilar trastuzumab (Zedora), unless recurrence or death. Safety outcomes will be recorded. Efficacy outcomes include invasive relapse-free survival (IRFS) rate at 18, 24, 30 and 36 months treatment initiation. Given the inexistence of a specific hypothesis to be tested, sample size was based on the accuracy of the two-sided 95% confidence interval (95% CI) for the invasive disease relapse-free survival rate. Results: In development countries such as as Brazil, oncology treatments with biological drugs have high costs and represent an import ibarrier to patients access to anti HER2 therapy. The use of biosimilars may result in significant health care savings. Conclusions: Considering the HERITAGE study, in which biosimilarity was clearly demonstrated between the reference monoclonal antibody and the biosimilar, we do expect to find the same safety and efficacy profile.

Citation Format: Leandro Alves, Débora Gagliato, Mayara de Paula, Ana Carolina Cardoso, Alexandre Alcantara, Maristela Precivale, Vivienne Castilho. A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-05.
Abstract P1-01-10: Positron emission mammography in assessment of the clinicopathological characteristics of breast cancers
Authors: Ito Jun , Sato Toshihiko
Published: March 2020

Background: Breast cancer is the most prevalent malignant neoplasm in women. Early detection and personalized treatment are very important to decrease mortality. Positron emission mammography(PEM) is a newly developed breast imaging technology using the positron emission tomography(PET) radiopharmaceutical 18F-fluoro-deoxy-D-glucose(18FDG). We investigated the correlation between PEM and known prognostic markers, including estrogen receptor(ER), progesterone receptor(PR), human epidermal growth factor receptor(HER2) status, tumor histology, nuclear grade, and the number of Ki-67-positive tumor cells/10 HPF(Ki-67 index). Methods: Fifty-eight patients were included in this study. PEM imaging was performed on a commercially available PEM unit. Maximum PEM uptake value(PUVmax) and lesion-to-background(LTB) ratio were determined. All resected specimens were evaluated by our institution’s pathology department. PUVmax and LTB ratios were compared with ER and PR status, tumor histology, and nuclear grades. The correlation coefficients between maximum PEM uptake value or LTB and the Ki-67 index were calculated. Results: PUVmax values were significantly different between ductal carcinoma in situ and invasive ductal carcinoma(P = 0.033). PUVmax and LTB showed significant differences between nuclear grade 1 and nuclear grade 3(PUVmax: P = 0.027, LTB: 0.0043). PUVmax, LTB, and Ki-67 index correlated significantly; PUVmax and Ki-67 index: correlation coefficient = 0.558, P = 0.000125; LTB and Ki-67 index: correlation coefficient = 0.572, P = 0.000075. Conclusions: PUVmax and LTB showed remarkable correlation with nuclear grades and the Ki-67 index, suggesting PEM’s utility in assessing the clinicopathological characteristics of breast cancer.

Citation Format: Jun Ito, Toshihiko Sato. Positron emission mammography in assessment of the clinicopathological characteristics of breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-10.
Abstract P1-13-02: Dynamic changes in high-sensitivity cardiac troponin I in response to anthracycline-based chemotherapy-The Cardiac Care Trial pilot data
Authors: Oikonomidou Olga , Tzolos Evangelos , Adamson Philip D , Hall Peter S , MacPherson Iain R , MacLean Morag , Lewis Steff , McVicars Heather , Newby David E , Mills Nicholas L , Lang Ninian , Henriksen Peter A
Published: March 2020

BACKGROUND Treatment advances have improved cancer-related outcomes and shifted interest towards minimising long-term iatrogenic complications, particularly chemotherapy-related cardiotoxicity. High-sensitivity cardiac troponin I (hs-cTnI) assays accurately quantify very low concentrations of plasma troponin and enable early detection of cardiomyocyte injury prior to development of myocardial dysfunction. The profile of hs-cTnI in response to anthracycline-based treatment has not previously been described. PATIENTS AND METHODS This was a multi-centre prospective observational cohort study. Female patients with newly-diagnosed invasive breast cancer scheduled to receive adjuvant or neo-adjuvant anthracycline-based (epirubicin) chemotherapy were recruited. Blood sampling was performed before, during and 24 hours after each treatment cycle. Plasma hs-cTnI concentrations were measured using the Abbott ARCHITECTSTAT assay (limit of detection 1.2 ng/L, coefficient of variation ≤10% at 4.7 ng/L, 99th centile upper reference limit in women 16 ng/L). RESULTS We recruited 78 women with a mean (standard deviation) age of 53.6 (9.6). The median (IQR) baseline troponin concentration was 1 (1 to 4) ng/L and median (IQR) cumulative epirubicin dose was 394 (300 to 405) mg/m2. Following an initial 33% fall 24 hours following anthracycline dosing (p <0.001), hs-cTnI concentrations increased by a median of 50% (p<0.001) with each successive treatment cycle. In total, 45 patients had troponin measured immediately prior to the sixth treatment cycle of whom 21 (46.6%) had hs-cTnI concentrations ≥16 ng/L indicating myocardial injury. Plasma hs-cTnI concentrations prior to the second treatment cycle were a strong predictor of subsequent myocardial injury. CONCLUSIONS Cardiotoxicity arising from anthracycline therapy is detectable in the earliest stages of breast cancer treatment and is cumulative with each treatment cycle. More than one third of patients will develop biochemical evidence of chronic myocardial injury with plasma hs-cTnI concentrations above the 99th centile upper reference limit. This injury is most reliably determined from blood sampling performed before rather than during or after each treatment cycle.

Citation Format: Olga Oikonomidou, Evangelos Tzolos, Philip D Adamson, Peter S Hall, Iain R MacPherson, Morag MacLean, Steff Lewis, Heather McVicars, David E Newby, Nicholas L Mills, Ninian Lang, Peter A Henriksen. Dynamic changes in high-sensitivity cardiac troponin I in response to anthracycline-based chemotherapy-The Cardiac Care Trial pilot data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-13-02.
Abstract P1-20-10: The role of micro-CT in imaging breast cancer specimens
Authors: Tiwari Ankur , DiCorpo Daniel , Hughes Kevin , Michaelson James
Published: March 2020

Background: The goal of breast cancer surgery is to remove all cancer with a minimum of normal tissue, but the absence of full 3-dimensional information on the surgical specimen makes this difficult to achieve. Method: Micro CT is a high resolution, X-ray, 3D imaging method, used principally in material science and industry but little used in medicine. Results: We imaged and analyzed 173 partial mastectomies by Micro-CT (129 ductal carcinomas, 14 lobular carcinomas, 28 DCIS). Imaging was simple and rapid. Size of cancer image on Micro-CT was very similar to the size of cancer at specimen dissection. Micro-CT images of surgical specimens in cassettes revealed sizes and shapes very similar to cancer later seen on the slide. Micro CT images of multicentric/multifocal cancers appeared as separate, clearly non-contiguous, masses. Additional image realization was carried out with image analysis software, with which we created a variety of three-dimensional image visualizations seen by rotation, slicing, and various degrees of transparentness, achieved by volume rendering with adjustment of opacity and maximum intensity projection imaging modified by the transfer function, making viewing through the 3D mass possible. Video can be seen at https://youtu.be/1hyNmFDidO4. Micro-CT assessment found cancer to touch edge in 134 (77%) of cases, while assessment of the microscope slides revealed positivity in 114 (66%) of cases. Cases judged by the pathologist to be margin positive were margin positive by Micro CT 93% the time. Cancer occupied 0.45% of surface area for “Micro-CT-Only-Positive Cases” but more than three times as much space, at 1.55% when both the pathologist and the Micro-CT suggested cancer at the edge. Conclusions: Micro-CT provides full 3D images of partial mastectomy specimens, allowing one to identify, in a few minutes, and thus while the patient is in OR, margin positive cases, with information on where cancer touches the edge, in a fashion more accurate than possible from the histology slides alone.

Citation Format: Ankur Tiwari, Daniel DiCorpo, Kevin Hughes, James Michaelson. The role of micro-CT in imaging breast cancer specimens [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-10.
Abstract P1-20-28: Intraoperative margin status in breast conserving surgery - A novel 3D evaluation using tomosynthesis
Authors: Nakad Bothaina , Matter Ibrahim , Simovici Paula , Milevsky Daria , Greg Oksana , Sroka Gideon , Brodsky Asia
Published: March 2020

Background: Margin status remains a debatable issue in breast cancer surgery, accounting for a 10-40% re-excision rate. Accurate intraoperative assessment of margin status enables one step surgery, lowers re-excision rates and offers better surgical and cosmetic outcomes for the patient. We present a novel 3D intraoperative evaluation using Screen Vision and Computed Tomosynthesis.

Methods: Our standard suture-guided orientations for a lumpectomy in 36 patients (SG group) undergoing BCS was compared to the new 3D orientation using the Screen Vision, a plastic box, with a two-dimensional axis system combined with three-dimensional tomosynthesis, in the first 26 patients operated with this technique (3D group). We defined clear margins as “no ink on tumor” for invasive carcinoma, and more than 2 mm distance for ductal carcinoma in situ. The margin status and the re-excision rates were recorded, for both benign and malignant lesions.

Results: The margin-expansion rate in the first operation according to intra-operative margin status imaging, was 6/36 (16%) in the SG group compared to 9/26 (34%) in the 3D group. Additional margin-expansion according to clinical suspect in spite of negative imaging status was performed in 14/36 (28%) in the SG group and 8/26 (30%) in the 3D group. The re-lumpectomy rate was 4/36 (11%) in the SG group and 2/26 (7%) in the 3D group.

Conclusions: This method of combined Screen Vision and computed tomosynthesis presents easier orientation of surgical specimens, with better intra-operative analysis of surgical margins. It might have a role in improving intra-operative margin status imaging, with subsequent lowering of re-lumpectomy rates.

Citation Format: Bothaina Nakad, Ibrahim Matter, Paula Simovici, Daria Milevsky, Oksana Greg, Gideon Sroka, Asia Brodsky. Intraoperative margin status in breast conserving surgery - A novel 3D evaluation using tomosynthesis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-28.
Abstract P2-02-02: Lack of screening mammography and black race are associated with late-stage breast cancer diagnosis in safety-net setting
Authors: Mendez Marissa A , Cheng An-Lin , Ahmadiyeh Nasim
Published: March 2020

Importance: In our urban safety-net hospital (SNH) setting, we see approximately three times more late-stage (stage III and IV) breast cancer at diagnosis than the rest of the country. Breast cancers diagnosed at later stages have lower survival than those diagnosed at earlier stages. The aim of this study is to determine the factors associated with late-stage breast cancer diagnosis in our SNH setting. Method: This is a retrospective study of all breast cancer cases diagnosed or treated at the primary SNH in the Kansas City, MO metro area between January 2011-July 2018 (n=615). All female breast cancer patients diagnosed with early-stage (stage 0 or I, n=314) or late-stage (stage III or IV, n=98) disease were included. Those diagnosed at stage II (n=176), recurrent breast cancer (n=20) or with conflicting or unknown stage (n=27) were excluded. Variables analyzed: clinical TNM stage at diagnosis, age, race, insurance type, zip code, tumor subtype, whether patient presented with symptoms, whether a screening mammogram was obtained in the two years prior to diagnosis, and whether the patient was referred from outside our institution, or internally. Median household income and distance to treating facility were imputed from patient-level zipcode data. Multiple logistic regression was performed to determine the variables that contributed the most to the late-stage at diagnosis. Results: Three variables were significantly associated with late-stage diagnosis in the multiple regression: not having had a screening mammogram within two years (p<0.0001, OR 0.132, CI= 0.063, 0.277), being black (p= 0.0051, OR 2.549, CI = 1.325, 4.904), and having HER2 positive disease (p=0.0213, OR=2.695, CI= 1.159, 6.265). A race by tumor marker interaction was examined, and was not found to be significant. Conclusions: In our safety-net hospital setting, not having a screening mammogram in the two years prior to a breast cancer diagnosis was the most significant factor associated with late-stage at diagnosis, followed by being black. Screening mammography ought to be actively promoted in safety-net hospital settings with excess late-stage diagnosis. Black women may need different risk-based screening guidelines.

Citation Format: Marissa A Mendez, An-Lin Cheng, Nasim Ahmadiyeh. Lack of screening mammography and black race are associated with late-stage breast cancer diagnosis in safety-net setting [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-02-02.
Abstract P2-13-04: Risk of osteoporosis and osteoporotic fracture in breast cancer survivors: A nation-wide study
Authors: Chung Il Yong , Lee Jihyoun , Alqudaihi Heba , Lee Jong Won , Son Byung Ho , Ahn Sei Hyun , Lee Ji Sung
Published: March 2020

Background: Referring to American Society of Clinical Oncology (ASCO) 2015 guidelines, they recommend bone screening every two years for premenopausal women receiving tamoxifen, considering it as a risk factor for developing osteoporosis. This nationwide study aimed to investigate the incidence of osteoporosis and osteoporotic fractures, and to assess whether the known factors increase the risk of osteoporosis and/or osteoporotic fractures among breast cancer survivors in South Korea.

Methods: A nationwide retrospective study was conducted using the Health Insurance Review and Assessment Service (HIRA) data. The incidence rates of osteoporosis and osteoporotic fracture were calculated by dividing the number of incident cases by the total follow-up period (person-years). The risk factors for osteoporosis and osteoporotic fracture were investigated using Cox proportional hazard regression models.

Results: From Jan 2009 to Dec 2014, a total of 47,649 breast cancer survivors were included in this analysis. During the study period, 5,955 osteoporosis events were observed from 252,396 person-year. The incidence rate of osteoporosis in breast cancer survivors was 23.59 per 1000 person-year (95% CI 23.00 - 24.20). Osteoporotic fracture incidence was assessed 2.40 per 1000 person-year (95% CI 2.23 - 2.60), with 647 events out of 269,075 person-years. In age<40 subgroup, use of ovarian function suppression (OFS) was significantly related to incidence of osteoporosis (Incidence rate 7.06 95% CI 5.47 - 9.11). However, the use of tamoxifen did not show an increased risk of osteoporosis (HR 1.24, 95% CI 0.85 - 1.82). Nine osteoporotic fracture was found in 7,121 patients in age under 40. In 40-49 age group, use of chemotherapy (HR 1.41, 95% CI 1.24-1.60, p<.0001), aromatase inhibitor (HR 2.45, 95% C.I. 2.05- 2.92, p<.0001), and OFS (HR 1.19, 95% CI 1.01-1.40, p =.0113) showed a significant increase of osteoporosis. Osteoporotic fracture were associated with use of AI and OFS in 40-49. Use of tamoxifen significantly decreased osteoporosis diagnosis in age 40-49, 50-59, and 60-69. Tamoxifen was also related to decreased incidence of osteoporotic fracture in age 40-49 (HR 0.49, 95% CI 0.31-0.76, p<.0001) and 50-59 (HR 0.37, 95% CI 0.23-0.60, p<.0001).

Conclusions: Tamoxifen is not associated with the increased risk of osteoporosis and osteoporotic fracture in breast cancer survivors.

Keywords: Breast Neoplasms, Survivorship, Osteoporosis, Bone Fractures, adverse effects

Citation Format: Il Yong Chung, Jihyoun Lee, Heba Alqudaihi, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Ji Sung Lee. Risk of osteoporosis and osteoporotic fracture in breast cancer survivors: A nation-wide study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-04.