bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C092: Axl inhibitor TP-0903 augments chemo- and immunotherapy efficacy in pancreatic cancer
Authors: Zhang Yuqing , Arner Emily N , Toombs Jason E , Foulks Jason M , Warner Steven L , Brekken Rolf A
Published: March 2020

Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the United States with a 5-year survival less than 9%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain a major challenge in the treatment of this disease. A key cellular program involved in therapeutic resistance is epithelial plasticity, which is associated with invasion and metastasis, as well as tumor cell evasion of immune surveillance. The receptor tyrosine kinase Axl is a critical driver of epithelial plasticity. High expression and activity of Axl is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic cancer. Here, we show that an Axl inhibitor (TP-0903), has anti-tumor and therapy sensitizing effects in pre-clinical models of pancreatic cancer. Syngeneic orthotopic models treated with TP-0903 alone or combination with gemcitabine and/or immune checkpoint blockade (anti-PD-1) reduced primary and metastatic tumor burden. Therapy with TP-0903, gemcitabine or the combinations significantly reduced primary tumor weight (p<0.05); however, anti-PD-1 alone had no effect. The incidence of micrometastasis was reduced from 62.5% in vehicle group to 14% with TP-0903, while the triple therapy (TP-0903/gemcitabine/anti-PD-1) completely eliminated micrometastasis in 9 animals. Furthermore, Nanostring analysis of the tumors demonstrated upregulated pro-inflammatory and immune activation genes in TP-0903-treated groups compared to the vehicle, indicating pharmacologic inhibition of Axl activation leads to a more immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD-1. Additionally, survival studies are being completed in genetically engineered mouse models treated with TP-0903 single agent or in combination with chemo- and immune-therapy. Consistent with the syngeneic model, preliminary evidence suggests that TP-0903 sensitizes the tumors to chemotherapy and immune checkpoint blockade, leading to a significant anti-tumor, anti-metastatic, and pro-survival effect on GEMMs of pancreatic cancer. These results support TP-0903 as a novel therapy for treatment of pancreatic cancer, a disease that is in desperate need for effective therapy.

Citation Format: Yuqing Zhang, Emily N Arner, Jason E Toombs, Jason M Foulks, Steven L Warner, Rolf A Brekken. Axl inhibitor TP-0903 augments chemo- and immunotherapy efficacy in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C092. doi:10.1158/1535-7163.TARG-19-C092
Abstract C125: Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins
Authors: Ohoka Nobumichi , Tsuji Genichiro , Shoda Takuji , Fujisato Takuma , Kurihara Masaaki , Demizu Yosuke , Naito Mikihiko
Published: March 2020

Targeted protein degradation using chimeric small molecules is an emerging modality in drug discovery. These compounds termed proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) contain two ligands connected with a linker: one ligand is specific for an E3 ubiquitin ligase, and the other ligand is specific for the target protein, and cross-link the E3 ligase and the target protein within the cell, thereby inducing the poly-ubiquitylation and proteasomal degradation of the target. Currently only a limited number of the E3 ligases, including IAPs, VHL and CRBN, can be recruited to the target proteins by this technology. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand for E3 ubiquitin ligase, we developed a novel class of chimeric molecules that recruit the aryl-hydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. We also developed a chimeric compound b-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using b-NF as an AhR ligand. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to recruit AhR E3 ligase to the target proteins.

Citation Format: Nobumichi Ohoka, Genichiro Tsuji, Takuji Shoda, Takuma Fujisato, Masaaki Kurihara, Yosuke Demizu, Mikihiko Naito. Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C125. doi:10.1158/1535-7163.TARG-19-C125
Abstract CN05-03: Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction
Authors: Bader Benjamin
Published: March 2020

Mutants of RAS are major oncogenes and occur in many human cancers, but efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins failed so far. We therefore focused on SOS1, the guanine nucleotide exchange factor (GEF) and activator of RAS. A combination of high-throughput and fragment screening resulted in the discovery of the first nanomolar SOS1 inhibitors, which effectively downregulate active RAS in tumor cells. The identification of novel potent and cellular active small molecule inhibitors will be presented which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1 and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. Compound BAY-293 selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations. In cells with wild-type KRAS, we observed complete inhibition of the RAS–RAF–MEK–ERK pathway. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of pERK activity by 50%. In preventing the reloading of with GTP the SOS-inhibitors strongly synergize with covalent inhibitors like ARS-853 or ARS-1620 targeting the mutant KRASG12C in its GDP-state. Together, the data indicate that inhibition of GEFs may represent a new viable approach for targeting RAS-driven tumors. Reference Hillig RC, et al. (2019) Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proceedings of the National Academy of Sciences 116(7):2551-2560

Citation Format: Benjamin Bader. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN05-03. doi:10.1158/1535-7163.TARG-19-CN05-03
Abstract LB-A21: Decouple the toxicity and efficacy of BJ-001, an integrin targeting IL-15
Authors: Wang Yanlan , Zhu Ziyan , Zhang Meng
Published: March 2020

IL-15 has been actively investigated for its potential in tumor immunotherapy. To enhance the anti-tumor activity of IL-15, BJ-001, an integrin targeting IL-15 was designed and studied. B-J001 showed tumor cell targeting without compromising IL-15 activity in vivo. In xenograft models, BJ-001 had potent anti-tumor activities. For majority of immunotherapies, increased efficacy is associated with increased toxicity. Interestingly, by monitoring the changes of immune cells and cytokines in vivo, the toxicity and efficacy of BJ-001 can be uncoupled. Increased efficacy of BJ-001 can be achieved without increasing toxicity. These studies may provide guidance for the therapeutic use of BJ-001, which is currently in Phase I human trial.

Citation Format: Yanlan Wang, Ziyan Zhu, Meng Zhang. Decouple the toxicity and efficacy of BJ-001, an integrin targeting IL-15 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A21. doi:10.1158/1535-7163.TARG-19-LB-A21
Abstract LB-B09: ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells
Authors: Gerosa Luca , Chidley Christopher , Froehlich Fabian , Sanchez Gabriela , Lim Sang Kyun , Muhlich Jeremy , Chen Jia-Yun , Baker Gregory J. , Schapiro Denis , Shi Tujin , Yi Lian , Nicora Carrie D. , Qian Wei-Jun , Wiley H. Steven , Sorger Peter
Published: March 2020

Anti-cancer drugs commonly target signal transduction proteins activated by mutation. In patients with BRAFV600E melanoma, small molecule RAF and MEK kinase inhibitors cause dramatic but often transient tumor regression. Emerging evidence suggests that cancer cells adapting by non-genetic mechanisms constitute a reservoir for the development of drug-resistant tumors. Here, we show that few hours after exposure to RAF/MEK inhibitors, BRAFV600E melanomas undergo adaptive changes involving disruption of negative feedback and sporadic pulsatile reactivation of the MAPK pathway, so that MAPK activity is transiently high enough in some cells to drive proliferation. ERK pulses are locally triggered by autocrine/paracrine factors in the local microenvironment so that ERK activity levels are low on average, but transiently high enough in patches of cells to explain the infrequent division characteristic of persister cells. Quantitative proteomics and computational modeling show that pulsatile MAPK reactivation is possible due to the co-existence in cells of two MAPK cascades: one driven by BRAFV600E that is drug-sensitive and a second driven by receptors that is drug-resistant. Paradoxically, this may account both for the frequent emergence of drug resistance and for the tolerability of RAF/MEK therapy in patients.

Citation Format: Luca Gerosa, Christopher Chidley, Fabian Froehlich, Gabriela Sanchez, Sang Kyun Lim, Jeremy Muhlich, Jia-Yun Chen, Gregory J. Baker, Denis Schapiro, Tujin Shi, Lian Yi, Carrie D. Nicora, Wei-Jun Qian, H. Steven Wiley, Peter Sorger. ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B09. doi:10.1158/1535-7163.TARG-19-LB-B09
Abstract LB-B11: Myeloid p38 MAPK promotes tumorigenesis by suppressing cytotoxic T cell recruitment
Authors: Choo Min-Kyung , Park Jin Mo
Published: March 2020

The last decade has seen explosive progress in understanding how tumor-associated macrophages (TAM) contribute to the development, metastasis, and therapy resistance of cancer. TAM and their molecular components are investigated as targets for cancer therapy. However, the precise mechanisms for their function remain to be fully elucidated. The p38 MAP kinase is known to play a pivotal role in cellular responses to stress, mitogenic stimuli, and immune signaling. Evidence from clinical observations and cell culture experiments reveals a role for p38 in many aspects of cancer and immunity. However, little is known about the functions of p38alpha, the most abundant and ubiquitously expressed p38 isoform, in TAM. Here we found that myeloid-specific p38alpha ablation resulted in a decrease in tumor incidence and multiplicity in a DMBA-TPA carcinogenesis model. Tumors from these mutant mice displayed markedly reduced proliferation and poorly developed blood vessels compared to those from control WT mice. Genome-wide expression analysis revealed that p38alpha ablation in macrophages resulted in enhanced CXCL9 expression, a chemokine crucial for cytotoxic T cell recruitment. Indeed, we observed greater number of tumor-infiltrating CD8+ T cells in myeloid-specific p38alpha-knockout mice. p38alpha indel mutations in THP-1 cells also led to elevated CXCL9 induction. TCGA data analysis revealed that higher intratumoral expression of CXCL9 was associated with prolonged survival of cancer patients, suggesting a beneficial effect of CXCL9 in human cancers. Next, we sought to identify the molecular mechanism linking p38alpha to the regulation of CXCL9 expression, and found that p38alpha directly phosphorylates and enables the induction of ATF3, a transcription factor that represses CXCL9 expression. Consistent with this finding, ATF3-deficient macrophages exhibited higher CXCL9 expression similar to p38alpha-deficient macrophages. Therefore, macrophage-specific targeting of p38alpha signaling may promote cytotoxic T cell recruitment to the tumor microenvironment and maximize the potential of checkpoint inhibitor and CAR T cell therapies and other therapeutic modalities that rely on tumor-killing CD8+ T cells.

Citation Format: Min-Kyung Choo, Jin Mo Park. Myeloid p38 MAPK promotes tumorigenesis by suppressing cytotoxic T cell recruitment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B11. doi:10.1158/1535-7163.TARG-19-LB-B11
Abstract PL03-03: Navigating gene-gene and drug-gene interaction landscapes underpinning the DNA damage response
Authors: Durocher Daniel
Published: March 2020

Loss of genome maintenance is a hallmark of cancers and targeting DNA and DNA repair processes have been mainstays of cancer therapy for decades. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells. I will highlight how these screens can be used to identify new genome stability factors, characterize drug responses and provide new insights into the genetic architecture of the genome stability network by identifying potentially actionable synthetic lethal genetic interactions. Given the focus of the conference, I will highlight how these screens can reveal new synthetic lethal interactions of therapeutic potential.

Citation Format: Daniel Durocher. Navigating gene-gene and drug-gene interaction landscapes underpinning the DNA damage response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL03-03. doi:10.1158/1535-7163.TARG-19-PL03-03
Abstract B15: Therapeutic potential of targeting amino acid metabolism in pancreatic cancer
Authors: Fernandez-Zapico Martin , Kim Dae Won , Philip Philip , Vandell Alexander , Eckard Jonathan , Korn Ron , Priore Giuseppe Del , Simeone Diane
Published: March 2020

Background: A wide range of cancers, including pancreatic cancer, display altered expression of amino acid transporter LAT-1. LAT-1 overexpression has been shown to be an important prognostic factor and predicts chemo resistance in pancreatic cancer (Kaira K, 2012; Altan B, 2018). Radiolabeled amino acids for PET imaging, including 3-18F-l-α-methyl-tyrosine ([18F] FAMT), have successfully leveraged cancer’s aberrant LAT1 expression and amino acid uptake for decades. SM-88 is a denatured D/L racemic form of α-methyl-tyrosine designed for selective uptake and disruption of protein synthesis in cancer cells, as well as disruption of catecholamine production via inhibition of tyrosine hydroxylase. Catecholamines have been reported to potentially have a role in driving pancreatic cancer progression and changes in the tumor immune status (Renz B, Cancer Cell 2018; Calvani M, Oncotarget 2014). Initial clinical and preclinical results with SM-88 indicate that this agent could pose a novel approach in the treatment of pancreatic cancer.

Methods and Results: Initial xenograft models of human gastrointestinal cancers using monotherapy SM-88 showed a >50% decrease in tumor growth at three weeks of treatment (p<0.05). Ongoing preclinical experiments are testing the full pharmacodynamic effects of SM-88 on pancreatic cancer cells, as well as potential effects on the tumor microenvironment due to catecholamine interruption. In results from the ongoing phase 2 trial of SM-88 in heavily pretreated metastatic pancreatic cancer patients, SM-88 has shown monotherapy antitumor activity based on RECIST 1.1 criteria. Additionally, 16/24 patients demonstrated a reduction in circulating tumor cells, with the median nadir decline of 63%. LAT1 has been reported to be important in EMT transition and mesenchymal cell survival (Holldorsson S, Cancer letters 2017); examination of the impact of SM-88 on this important emerging biomarker is ongoing.

Conclusion: Altered amino acid (LAT1) metabolism has been shown to be a negative prognosticator in pancreatic cancer outcomes and progression. Targeting LAT1 and amino acid pathways has been identified as a therapeutic approach in multiple cancers (Fuchs BC, Semin Ca Biol 2005). Initial and ongoing studies of SM-88 may clarify the potential utility of this approach in the treatment of pancreatic cancer.

Citation Format: Martin Fernandez-Zapico, Dae Won Kim, Philip Philip, Alexander Vandell, Jonathan Eckard, Ron Korn, Giuseppe Del Priore, Diane Simeone. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer [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 B15.
Abstract C18: TGF-beta blockade paradoxically activates non-SMAD signaling
Authors: Husain S. Mazher , Kansal Rita , Alvarez Marcus A. , Glazer Evan S.
Published: March 2020

Transforming growth factor-beta (TGF-B) activates a receptor leading to a critical signaling cascade in pancreatic ductal adenocarcinoma (PDAC) that results in cancer progression through epithelial-to-mesenchymal transition (EMT) and therapeutic resistance. This signaling is through both the canonical SMAD and non-SMAD proteins. Clinically, there exists a TGF-B paradox where TGF-B is a tumor suppressor in nonmetastatic PDAC but a tumor promotor in metastatic PDAC. We hypothesized that TGF-B receptor blockade helps explain the paradox leading to EMT and therapeutic resistance due to non-SMAD signaling. We investigated expression of proteins involved in non-SMAD TGF-B signaling in human PDAC cell lines with Western blot and in patient-derived organoids with immunofluorescence. Inhibition of the TGF-B receptor type 1 with galunisertib resulted in increased phospho-MAPK14 and phospho-Akt compared to controls. In metastatic PDAC, we also demonstrated that this results in increased levels of the activate beta-catenin complex. There were no changes to SMAD2 or SMAD3 phosphorylation. Our work demonstrates that despite blocking of the TGF-B receptor 1, phosphorylation of MAPK14 increases leading to non-SMAD signaling through Akt. Our data demonstrate that beta-catenin is the effector molecule for cancer progression. Our results also demonstrate a possible mechanism for the development of therapeutic resistance in patients with PDAC who undergo TGF-B receptor inhibition therapy.

Citation Format: S. Mazher Husain, Rita Kansal, Marcus A. Alvarez, Evan S. Glazer. TGF-beta blockade paradoxically activates non-SMAD signaling [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 C18.
Abstract C63: The analysis of microbiota composition between tumor and normal tissues in pancreatic cancer and the comparison with the public data of NCBI
Authors: Choi Hwi Wan , Kim Jinju , Kim Eo Jin , Jun Eunsung
Published: March 2020

Purpose: The translocation of gut bacteria and its derivatives may be an essential factor contributing to the various diseases of the pancreas. However, microbial function on the development and progression of pancreatic cancer is not clear and the research is still lacking. The aim of this study is to analyze the composition of microbiota in pancreatic cancer tissue and to compare the result with the existing public data.

Methods: We obtained the cancer and normal tissues from patients who underwent pancreatic cancer surgery in Korea (IRB: 2018-0710), and total bacterial genomic DNA was purified from tissue. Through the gene sequencing of 16S rRNA (V3-V4 lesion), we analyzed the quantitative and qualitative composition of microbiome. Then we compared the microbiome composition with public data of NCBI (SRP132007).

Results: We successfully performed the gene sequencing of 16s rRNA from 12 tumor tissues and 6 normal tissues. Based on the results obtained from the tumor and normal tissues, we compared the composition from the phylum to the species levels. We confirmed that there were significant differences in the microbiome composition of the tumor and normal tissues and identified various strains of 20 or more species with a high specificity in tumor or normal tissues. In addition, through the comparison with SRP132007 data, we confirmed a distinct difference between the two groups.

Conclusions: We have analyzed the patterns and characteristics of tumor or normal specific microbiomes through pancreatic cancer tissues. There is a clear difference between the two groups with environmental differences, even in the microbiomes of patients with the same disease. We expect to further clarify the importance of microbiomes in pancreatic cancer and point to the development of new therapies through further studies.

Citation Format: Hwi Wan Choi, Jinju Kim, Eo Jin Kim, Eunsung Jun. The analysis of microbiota composition between tumor and normal tissues in pancreatic cancer and the comparison with the public data of NCBI [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 C63.
Abstract ES2-2: Evolving opportunities to personalize radiation decisions - Guiding decisions to omit radiation after breast conserving surgery for invasive breast cancer
Authors: Speers C
Published: March 2020

Much as the development of molecularly based signatures (OncotypeDx®, MammaPrint®, ProSigna™, etc.) has revolutionized the decision-making process surrounding the need for adjuvant chemotherapy in women with early stage breast cancer, the development of prognostic and predictive signatures to determine the need and efficacy of radiation for women with breast cancer holds similar promise. While preliminary efforts to develop these signatures has been encouraging, much work remains in order to successfully translate these signatures into the clinic. In this educational session, we will review the current status of genomic-based signatures for radiation decision making. We will also review the barriers to clinical adoption and the molecularly stratified trials testing these signatures for treatment omission. Ultimately, for any of these tests to be translated into the clinic it will require demonstration of their accuracy and reproducibility as a test and perhaps more importantly, demonstration of clinical utility and an ability to improve outcomes for women with breast cancer. While not yet realized, the ongoing development of these signatures holds much promise as the field seeks to finally realize “personalized medicine” as it relates to radiation treatment for women with breast cancer.

Citation Format: C Speers. Evolving opportunities to personalize radiation decisions - Guiding decisions to omit radiation after breast conserving surgery for invasive 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 ES2-2.
Abstract ES2-3: Guiding selection of RT approach after lumpectomy
Authors: Shaitelman SF
Published: March 2020

Level I evidence supports the usage of adjuvant radiation therapy following breast conserving surgery for early stage breast cancer. Historically, this was typically delivered using standard fractionation whole breast irradiation. We will review multicenter, randomized controlled trials that support the use of hypofractionation in this setting. More recent level I data has also demonstrated excellent local control with partial breast irradiation for select, early stage breast cancers. In this educational talk we will review the local control and toxicity data for partial breast irradiation. International guidelines on the use of hypofractionated whole breast irradiation and partial breast irradiation will be discussed. We will aim to provide a framework for decision making when electing radiation technique in this setting.

Citation Format: SF Shaitelman. Guiding selection of RT approach after lumpectomy [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 ES2-3.
Abstract ES4-1: Adaptive Resistance to Hormonal Therapy
Authors: Fuqua S
Published: March 2020

While recurrences are delayed by the use of endocrine therapy (ET), resistance can evolve with the development of metastatic breast cancer (MBC) in about one-fourth of ER-positive patients. MBC is incurable with a median 5-year survival rate of less than 25%. We know that ET resistance can result from an adaptive process in which escape survival mechanisms are used to evade treatment. One of the best-characterized ET resistance mechanisms is transcriptional activation of growth factor receptor (GFR) signaling, and subsequent estrogen-independent activation of ER via “cross-talk” with downstream signaling from GFRs. We will discuss distinct mechanisms of ligand-independent activation of ER discovered using transcriptional profiling of metastatic, ET-resistant tumors. It is now estimated that ~20% of therapy-resistant MBCs contain ESR1 mutations. Recent data has also shown that mutations in the MAPK/RAS pathway and transcription factor regulatory programs (for example, MYC) only account for an additional 22% of recurrent breast tumors. Thus, acquired mutations alone do not account for the majority of ET resistance mechanisms in MBC. ER-positive breast cancer cell lines display profound transcriptional variability at the single cell level associated with the acquisition of therapy resistance. Recently, bulk and single cell RNA sequencing was used on sequential samples from patients with ER-positive, ET-resistant patients and identified RNA expression patterns that represented different cellular phenotypes, including an increased epithelial mesenchymal transition state that could provide a selective advantage for selective phenotypic subclones to dominate. We will focus our discussion of transcriptional reprograming as a major mechanism of ET resistance.

Citation Format: S Fuqua. Adaptive Resistance to Hormonal 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 ES4-1.
Abstract ES6-3: Breast cancer genetic testing: moving from cancer risk assessment to therapeutic biomarker
Authors: Balmaña J
Published: March 2020

In the last two decades germline genetic testing for breast cancer (BC) susceptibility has evolved from a single-gene analysis to a multigene cancer panel risk assessment tool. In addition, identifying a mutation in the BRCA1/2 genes may nowadays represent an opportunity for cancer targeted therapy. Current challenges in our routine clinical practice and for public health policies are to reconcile the implications derived from the identification of a hereditary cancer susceptibility that may impact beyond the person who is performing the genetic test, with and increasing and faster access to the test. Assessment of cancer risk was the first reason to incorporate germline BC genetic testing. As a consequence, mutation carriers are recommended specific screening and/or risk reduction options. While prophylactic bilateral salpingoophorectomy has shown a decrease in mortality and ovarian cancer-specific mortality, its role as a risk reduction option for breast cancer remains controversial. Radiologic imaging with magnetic resonance and mammogram has demonstrated beneficial in early detection of breast cancer, but risk reducing mastectomy may also be an option. Recent prospective data has shown that cancer risks differ between BRCA1 and BRCA2 mutation carriers, and that this estimation may be influenced by a combination of single-nucleotide polymorphism that constitute the polygenic risk score (PRS). Whether a more precise accuracy in cancer risk estimation in the short term (ie 5-10 years) may help to tailor screening and/or risk reduction options is unknown. As more BC-associated genes have been identified and technology has evolved, single gene testing has evolved to multigene panel testing. Available data suggests that patients can cope with multigene cancer panels although more research is needed to fully understand the psychosocial implications of multigene cancer panels, especially for those who have variants of unknown significance or moderate penetrance variants. Research is also needed to explore and develop communication models that maximize patients’ understanding and empower them to make informed decisions. The impact on reproductive-decision making will also be explored. Finally, a mutation in the BRCA1/2 genes is a predictive biomarker for targeted therapies in breast, ovarian, pancreatic and prostate cancer. Therefore, knowing the genetic status of our BC patients may influence their therapeutic options. The challenges and opportunities derived from new clinical scenarios that accompany these advances will be addressed during the educational session.

Citation Format: J Balmaña. Breast cancer genetic testing: moving from cancer risk assessment to therapeutic biomarker [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 ES6-3.
Abstract ES8-1: Adjuvant endocrine therapy in 2020: It's complicated
Authors: McCartney A , Leo A Di
Published: March 2020

Adjuvant endocrine therapy in 2020: It’s complicated Data regarding the use of adjuvant endocrine therapy in patients with hormone receptor-positive early breast cancer has grown over the past decades, and yet still uncertainty remains in management recommendations. In pre-menopausal women, treatment decisions are often driven by estimation of risk of recurrence, measured in terms of clinical and pathological parameters, algorithm-based prognostic modelling derived from breast cancer registries, molecular profiling and gene signature assays. Despite these significant advances, risk of distant disease recurrence is still over-estimated in a significant proportion of women. The addition of ovarian suppression to tamoxifen in pre-menopausal women has been shown to increase rates of both disease-free survival and overall survival than tamoxifen alone, with the use of the steroidal aromatase inhibitor exemestane producing further higher rates of freedom from recurrence. However, the addition of ovarian suppression in this generally low-risk population comes at the cost of increased adverse events and potential to interpose child-bearing years. Further to this, the SOFT/TEXT studies mandated five years of active treatment; little is known as to whether extended treatment beyond those five years would be comparatively equal, better or worse in terms of outcome endpoints.

In the post-menopausal population, the updated ASCO Clinical Practice Guideline suggests that all women with node-positive disease should be offered extended therapy including an aromatase inhibitor for a total of ten years, as well as women with node-negative disease possessing high-risk prognostic factors. The question of how best to identify those women who may fare equally well with de-escalated, shorter therapy remains open. The issue of adverse events and drug-related side effects, particularly in the setting of extended therapy, is relevant and may impact negatively on overall treatment compliance and quality of life. As such, the choice of endocrine therapy remains an important consideration, as is evidence that intermittent administration of aromatase inhibitors may be feasible in selected patients.

CDK4/6 inhibitors, administered in tandem with endocrine therapy, have radically changed the approach to managing metastatic endocrine receptor-positive disease. There is now much interest in moving these agents forward into the neoadjuvant and adjuvant setting, with a number of phase II and III trials ongoing. If positive data is consistently reported in adjuvant studies, this will undoubtedly create another layer of complexity to the clinical management of endocrine-sensitive disease.

Citation Format: A McCartney, A Di Leo. Adjuvant endocrine therapy in 2020: It's complicated [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 ES8-1.
Abstract OT1-08-05: Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM)
Authors: Leone Jose P , Trippa Lorenzo , Milisits Lindsey , Andrews Chelsea , Ligibel Jennifer , Parsons Heather , Bi Wenya L , Zhao Jean , Winer Eric P , Lin Nancy U
Published: March 2020

Background: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR.

Methods: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.

Citation Format: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin. Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM) [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 OT1-08-05.
Abstract OT3-02-03: Radiomics multi-parametric MRI of before and after neoadjuvant chemotherapy associated with axillary lymph node metastasis and prognostic in patients with breast cancer: A multicenter RBC-002 study
Authors: Yao Herui , Li ChenChen , Yu Yunfang , Xie Chuanmiao , Ouyang Jie , Tan Yujie , Lu Nian , Wang Ying , Zhao Jianli , Chen Kai , Ma Jiafan
Published: March 2020

Background: Axillary lymph node metastasis is a vital factor of prognosis in patients with invasive breast cancer. However, sensitivity and noninvasive for prediction of lymph node metastasis and survival after neoadjuvant chemotherapy is limited. This study aims to develop radiomics combining multi-parametric MRI before and after neoadjuvant chemotherapy to predict axillary lymph node metastasis and prognosis, as well as investigate the relationship between the radiomics and tumor microenvironment in invasive breast- cancer.

Methods: RBC-02 is a multicenter, ambispective cohort study proposes to build a clinical predictive model to predict axillary lymph node metastasis and prognosis in invasive-breast- cancer patients who received neoadjuvant chemotherapy. Patients are recruited from Sun Yat-sen Memorial Hospital of Sun Yat-sen University (training cohort), Sun Yat-sen University Cancer Center (validation cohort), and Tungwah hospital of Sun Yat-sen University (validation cohort) in China. Invasive breast cancer patients undergo multi-parametric MRI at baseline, then undergo multi-parametric MRI after received neoadjuvant chemotherapy for at least 4 cycles as planned. After the surgery, responses to neoadjuvant chemotherapy are determined according to the histopathologically examination of the surgically resected specimens. The model is built based on breast MRI signatures extracted and analyzed via deep machine- learning algorithm methods. The correlation between radiomics features and tumor microenvironment is also planned to investigate. Decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the radiomics nomogram, which is built with a multivariate logistic regression model. The primary endpoint is disease-free survival. Secondary endpoints include pathological complete response, pathological axillary lymph node status, and overall survival. The trial is registered with ClinicalTrials.gov, number NCT04004559, and Chinese Clinical Trail Registry, number ChiCTR1900024113.

Citation Format: Herui Yao, ChenChen Li, Yunfang Yu, Chuanmiao Xie, Jie Ouyang, Yujie Tan, Nian Lu, Ying Wang, Jianli Zhao, Kai Chen, Jiafan Ma. Radiomics multi-parametric MRI of before and after neoadjuvant chemotherapy associated with axillary lymph node metastasis and prognostic in patients with breast cancer: A multicenter RBC-002 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 OT3-02-03.
Abstract P1-09-06: Metabolic coupling in phyllodes tumor of the breast and its correlation to tumor progression
Authors: Leee Ji Shin , Kim Nah Ihm , Park Min Ho
Published: March 2020

Background: Markers of metabolic coupling have been associated with clinical outcomes in numerous human cancers, including breast cancer. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has been rarely described in phyllodes tumors (PTs) of the breast. Materials and methods: One hundred-one PTs (60 benign, 26 borderline, and 15 malignant) and 9 breast tissues with no pathological lesions were analyzed. Automated immunohistochemical staining for CAV-1, MCT1, and MCT4 was performed using tissue microarray blocks, and their expressions were assessed in both stromal and epithelial components. Results: Compared with normal breast, CAV-1 expression in PTs showed a significant decrease in stromal component (P < 0.001). MCT1 expression was significantly increased in both epithelial and stromal components of PTs compared to normal breast (P < 0.001 and P < 0.001, respectively). Stromal MCT1 and MCT4 expression was different according to the tumor grade of PTs and stromal MCT1 expression tended to increase with increasing tumor grade (P < 0.001). Although not statistically significant, stromal CAV-1 expression tended to decrease with increasing PTs grade. The recurrence rate was higher in the stromal MCT1-positive groups (19.2%, 14/73) than in the stromal MCT1-negative groups (3.9%, 1/28) (P < 0.05). Conclusions: This result suggested that changes of CAV-1, MCT1, and MCT4 may be associated with tumorigenesis and progression of PTs of the breast. Keywords Phyllodes tumor, CAV-1, MCT 1, MCT4, Metabolic coupling.

Citation Format: Ji Shin Leee, Nah Ihm Kim, Min Ho Park. Metabolic coupling in phyllodes tumor of the breast and its correlation to tumor progression [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 P1-09-06.
Abstract P1-09-08: Development and characterization of PTEN IHC assay for testing breast cancer patients specimens
Authors: Gong Hua , Pacia Emmanuel , Manjeshwar Sharmila , Chen Beiru , Li Xun , Dabbas Bashar , Lameh Jelveh , Babbar Naveen , Tangri Shabnam
Published: March 2020

Background: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that is a major negative regulator of the Phosphatidylinositol 3-kinase (PI3K) pathway. Loss of PTEN protein expression has been mechanistically linked to tumor progression. Blocking the PI3K pathway might inhibit the growth and proliferation of cells that have deletions in PTEN. Thus characterization of PTEN expression in patient tumor samples may assist prediction of potential response to PI3K inhibitor therapies.

Methods: We developed and validated an immunohistochemical assay on Ventana BenchMark XT to detect PTEN in formalin fixed and paraffin-embedded (FFPE) tissue by utilizing a rabbit monoclonal antibody (clone 138G6) from Cell Signaling Technologies that recognizes the carboxy-terminal domain of PTEN. PTEN immunohistochemical staining was performed on 1577 breast tumor specimens to determine PTEN protein loss. A subset of these cases (n=663) was also assessed for PTEN mutation.

Results: Cellular localization of PTEN expression was observed in both the cytoplasm and the nucleus. Both cellular compartments were scored and used in the staining intensity determination. We observed that PTEN staining is sensitive to variation in tissue handling, fixation and antigen retrieval. PTEN staining was affected significantly by antigen retrieval method. Optimal staining conditions were determined to be 1:60 antibody dilution using Citrate pH 6.0 as antigen retrieval buffer. In a cohort of 1577 hormone receptor positive HER2-negative locally advanced or metastatic breast cancer patients, loss of PTEN protein was observed in 8.6% (135/1577) of patients. There was a positive correlation between PTEN mutation rate (17 out of 66 PTEN IHC positive cases vs 14 out of 587 negative cases) and loss of PTEN protein expression. PTEN loss was observed to correlate with better clinical response to PI3K inhibitor.

Conclusions: Pre-analytical handling of samples is important for PTEN IHC staining. PTEN mutations and insertions/deletions contribute to PTEN protein loss. This study validates a simple method to interrogate PTEN status in clinical specimens and supports the utility of this test in selecting patients who are likely to respond to PI3K inhibitor treatment.

Citation Format: Hua Gong, Emmanuel Pacia, Sharmila Manjeshwar, Beiru Chen, Xun Li, Bashar Dabbas, Jelveh Lameh, Naveen Babbar, Shabnam Tangri. Development and characterization of PTEN IHC assay for testing breast cancer patients 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 P1-09-08.
Abstract P1-10-25: The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab
Authors: Hayashi Tomomi , Watanabe Junichiro , Nakamoto Shyogo
Published: March 2020

Purpose: Many reports have provided real-world evidence that inflammatory response biomarker (IRB) scores may be useful for predicting the therapeutic effect of chemotherapy and the prognosis for various neoplasms. The aim of this retrospective study was to evaluate the clinical roles of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) as predictive factors of Paclitaxel + Bevacizumab (PB) therapy for patients with HER2-negative metastatic breast cancer (HER2-MBC).

Methods: We reviewed the medical records of 123 HER2-MBC patients who underwent PB therapy in our institute. The NLR, PLR, and LMR were calculated from blood cell counts prior to the initiation of PB therapy. The optimal cut-off point of each ratio was determined according to receiver operating characteristic (ROC) curves. The Kaplan-Meier test and Wilcoxon test were used to analyze the progression- free survival (PFS) and overall survival (OS). The differences were considered significant for p < 0.05.

Results: The median age at the start of treatment was 53 years old. Of the 123 patients, 98 (80%) were hormone- receptor- positive, and 82 (67%) had multiple (>2) metastatic sites. The median PFS was 7.0 months (95% confidence interval, 5.8-8.4), and the median treatment line before PB therapy was 0 (range: 0-10). The cut-off points of the NLR, PLR, and LMR for the PFS and OS were 2.7, 178, and 3.0, respectively. We found that a high NLR and low LMR were associated with a poor PFS (NLR, median 6.5 vs. 8.4 months, p=0.04: LMR, median 5.6 vs. 8.1 months, p=0.02), and a high LMR was associated with a superior OS (median, not reached vs. 187 months, p=0.02) and 10- year survival rate (76.4% vs. 52.9%, p=0.02). The PLR showed no relationship with the PFS or OS.

Conclusion: The NLR and LMR might be independent biomarkers, i.e. predictive factors, for patients with HER2-MBC receiving PB therapy in the real world. A prospective study to confirm the utility of those biomarkers is warranted.

Citation Format: Tomomi Hayashi, Junichiro Watanabe, Shyogo Nakamoto. The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab [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 P1-10-25.