bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C25: Aspiration liquid biopsy (ALB) of pancreatic cancer (PC)
Authors: Kashintsev Aleksei , Kokhanenko Nikolai , Imyanitov Evgeniy , Proutski Vitaliy , Granstrem Oleg , Solovieva Lyudmila , Medvedev Konstantin , Pavelets Konstantin , Anisimov Sergey
Published: March 2020

Introduction: Early detection of PC is the main clue for improving results of treatment. Liquid biopsy (LqB) is the most promising method of detection of disease in a screening context, but selection of biologic material for that is not a resolved problem. Pancreatic juice is the highly specific substance for that aim. However, its collection and analysis are associated with many technical difficulties.

Materials and Methods: For pancreatic juice collection we developed a method of ALB using a proprietory pancreatodigestive stent. This stent allows for active aspiration of pancreatic juice. We had recruited 15 patients with verified PC before treatment. Placement of the stent was performed by endoscopy and followed by collecting of pancreatic juice in sterile container at 4o C. After collecting sufficiently large volume of the material, we centrifugated it and made cell-block for cytologic examination.

Results: ALB was performed in all 15 cases without any complications. Placement and removal of the stent was atraumatic and without technical problems. However, only in 1 sample out of 15 did we detect atypical cells using standard cytologic examination.

Conclusion: We present new methodology for collecting biomaterial potentially useful for the early diagnosis of pancreatic cancer. This method is simple and can be easily replicated. Its application does not require high-quality specialized medical centers and personnel and can be performed in standard gastroenterologic clinics. Collected samples can be easily stored. Furthermore, in addition to cells it allows to obtain the liquid fraction of pancreatic juice that could be used for the detection of tumor DNA.

Citation Format: Aleksei Kashintsev, Nikolai Kokhanenko, Evgeniy Imyanitov, Vitaliy Proutski, Oleg Granstrem, Lyudmila Solovieva, Konstantin Medvedev, Konstantin Pavelets, Sergey Anisimov. Aspiration liquid biopsy (ALB) of pancreatic cancer (PC) [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 C25.
Abstract C31: The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness
Authors: McElyea Samantha , Korc Murray
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant malignancy that harbors several key driver mutations at a high frequency (e.g., KRAS, TP53, CDKN2A, and SMAD4<), as well numerous driver mutations that occur at a relatively low and variable frequency among patients with PDAC. Heparan-sulfate proteoglycans (HSPGs) constitute a large family of glycanated proteins that modulate numerous cellular processes and interact with components of the extracellular matrix (ECM) and with heparin-binding growth factors such as heparin binding EGF-like growth factor (HBEGF) that activates the EGF receptor (EGFR) and transforming growth factor beta (TGF-beta) moieties. Syndecan-4 (SDC4) is a transmembrane HSPG that has critical roles in focal adhesion formation, cytoskeletal attachment, cell contractility and motility, and cell signaling, especially in relation to pathways activated by heparin-binding growth factors. To date, the role of SDC4 in PDAC has not been clearly elucidated. Yet, data from 1,034 PDAC samples in The Cancer Genome Atlas (TCGA) revealed that 19% of these samples exhibited altered SDC4 expression, a majority of which were either gain-of-function or amplification alterations often co-occurring with enhanced TGF-beta1 expression, thus underscoring the potential importance of SDC4 in PDAC. Given that TGF-beta1 increases SDC4 expression whereas SDC4 modulates TGF-beta1 actions and interacts with EGFR, we sought to test the hypothesis that SDC4 contributes to PDAC’s progression. Accordingly, we established a novel genetically engineered mouse model (GEMM) of PDAC in which pancreas-specific Cre-mediated expression of oncogenic Kras was combined with deletion of a conditional Ink4a/Arf allele in the presence or absence of SDC4: Pdx1-Cre;LSL-KrasG12D;Ink4a/Arflox/lox;Sdc4-/-, termed KIS4-/-C mice. By comparison with control KIS4 animals, KIS4-/-C mice exhibited attenuated pancreatic tumor growth and markedly prolonged survival. There was attenuation of cancer cell proliferation in the tumors, as determined by Ki67 staining, as well as decreased desmoplasia as evidenced by Mason trichrome staining. By contrast, KIS4+/-C animals with heterozygous loss of SDC4 only exhibited a modest survival advantage by comparison with control KIS4 animals. Taken together, these findings suggest that strategies based on suppressing SDC4 expression and/or function may yield new therapeutic approaches in PDAC. (Supported in part by National Cancer Institute grant CA-075059 to M.K.)

Citation Format: Samantha McElyea, Murray Korc. The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness [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 C31.
Abstract C52: The radioprotector GC4419 enhances the response of PDAC tumors to high dose per fraction radiation exposure
Authors: Story Michael D. , Sishc Brock J.
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, with an estimated 5-year overall survival rate of ~6%. While surgery followed by adjuvant therapy is the standard of care, most patients present with advanced disease. Recent clinical trials have demonstrated that the traditional radiation dose limit of 50.4 Gy to tumors located at the head of the pancreas is not sufficient to generate tumor control at doses tolerable to the jejunum; however, doses exceeding 60 Gy, particularly when delivered as stereotactic body radiation therapy (SBRT), drastically enhance progression free-survival at 2 years. Here, we present evidence that the radioprotector GC4419 (Galera Therapeutics, St. Louis, MO) whose enantiomer, GC4403, has demonstrated radioprotective properties against GI toxicity, sensitizes PDAC cells and xenografts to radiation exposure. Furthermore, combination therapy with immune oncology agents targeting the PD-L1 pathway enhanced the response of Panc02 tumors (syngeneic to C57.BL/6 mice) to combined radiation and immune therapy. These results present the foundation for a newly initiated dose-escalation clinical trial for treating PDAC tumors with GC4419 and SBRT.

Citation Format: Michael D. Story, Brock J. Sishc. The radioprotector GC4419 enhances the response of PDAC tumors to high dose per fraction radiation exposure [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 C52.
Abstract C57: Organoid profiling identifies common responders to chemotherapy in pancreatic cancer
Authors: Tiriac Herve , Belleau Pascal , Engle Dannielle , Plenker Dennis , Deschenes Astrid , Somerville Tim , Froeling Fieke , Moffitt Richard , Knox Jennifer , Krasnitz Alexander , Gallinger Steven , Tuveson David
Published: March 2020

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

Citation Format: Herve Tiriac, Pascal Belleau, Dannielle Engle, Dennis Plenker, Astrid Deschenes, Tim Somerville, Fieke Froeling, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David Tuveson. Organoid profiling identifies common responders to chemotherapy 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 C57.
Abstract PR12: The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice
Authors: Engle Dannielle , Tiriac Herve , Rivera Keith , Pommier Arnaud , Whalen Sean , Oni Tobiloba , Alagesan Brinda , Lee Eun , Yao Melissa , Lucito Matthew , Spielman Benjamin , Yu Kenneth , Grutzmann Robert , Aust Daniela , Gimotty Phyllis , Pollard Katherine , Hruban Ralph , Goggins Michael , Pilarsky Christian , Park Young , Pappin Darryl , Hollingsworth Michael A. , Tuveson David
Published: March 2020

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and b1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewis a, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.

This abstract is also being presented as Poster C16.

Citation Format: Dannielle Engle, Herve Tiriac, Keith Rivera, Arnaud Pommier, Sean Whalen, Tobiloba Oni, Brinda Alagesan, Eun Lee, Melissa Yao, Matthew Lucito, Benjamin Spielman, Kenneth Yu, Robert Grutzmann, Daniela Aust, Phyllis Gimotty, Katherine Pollard, Ralph Hruban, Michael Goggins, Christian Pilarsky, Young Park, Darryl Pappin, Michael A. Hollingsworth, David Tuveson. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice [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 PR12.
Abstract BS1-2: Genome regulation by long noncoding RNA genes
Authors: Chang HY
Published: March 2020

The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. I will discuss genome-scale strategies to discover and characterize lncRNAs, including RNA chemical modifications and RNA structures. LncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and target these enzymatic activities to appropriate locations in the genome. Long noncoding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. A new emerging theme is that DNA elements that mediate lncRNA expression can also have powerful effects in controlling chromatin neighborhoods, which alter oncogene expression and activity. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs in human diseases.

Citation Format: HY Chang. Genome regulation by long noncoding RNA genes [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 BS1-2.
Abstract CS1-2: Emerging Therapies for HER2 Positive Breast Cancer
Authors: Modi S
Published: March 2020

HER2 targeted therapies have had a significant impact in improving clinical outcomes and survival for patients with HER2 positive breast cancer. However, new therapies for patients with refractory disease are still needed. Based on a greater understanding of the biology and mechanisms of resistance, a new generation of HER2 agents is evolving. Here we provide an overview of promising novel therapies, both proven and in development, for the treatment of refractory HER2 positive breast cancer. This will include a review of antibody drug conjugates, tyrosine kinase inhibitors, immune strategies as well as future combination therapies.

Citation Format: S Modi. Emerging Therapies for 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 CS1-2.
Abstract ES11-1: The biology and plasticity of residual disease after neoadjuvant treatment
Authors: Perou C
Published: March 2020

Breast cancer neoadjuvant treatment is becoming more prevalent, and has emerged as a valuable tool to downstage tumors, to identify predictors of responsiveness, and to potentially adapt therapeutic interventions to that individual’s residual disease if present. This has led to increasingly complex patient management and the development of many clinical trials specifically designed for those with residual disease. However, the basic biology of residual disease, how it relates to pre-treated disease, and how it could be used for prognostic and redictive benefits, are still relatively unknown.

In this session I will cover a number of studies that have specifically studied breast tumors before and after neoadjuvant treatment, with a focus on changes within the tumor cell population, including acquisition of epithelial-to-mesenchymal (EMT) and stem-like properties. In addition, alterations to immune cell dynamics in the tumor microenvironment, the plasticity of post-treatment phenotypes, and how these features impact the treatment paradigm based upon residual disease, will also be discussed.

Multiple factors likely contribute to the poor prognosis associated with residual disease. Human breast tumors that remain following either chemotherapy, or endocrine therapy, often show an enrichment of gene expression signatures associated with tumor-initiating cells and EMT, suggesting that intrinsic tumor characteristics may contribute to selection of resistant populations. Additionally, residual tumors may show a variety of genomic aberrations at higher frequency than found in primary tumors, suggesting that resistance pathways may be selected for during neoadjuvant treatment. Tumor extrinsic factors, particularly the interaction between tumor and immune cells, are also altered by breast cancer neoadjuvant therapies. Nevertheless, there is hope that these residual disease specific alterations may provide key susceptibilities to other treatments.

Lastly, defining predictive biomarkers from residual disease has been difficult. In addition to the variety and complexity of resistance mechanisms that lead to residual disease, questions regarding tumor plasticity and the duration of post-treatment changes complicate the analysis of residual breast cancers specimens. An improved understanding of the biology of residual breast cancers will be critical as we develop novel treatment strategies for those with residual disease.

Citation Format: C Perou. The biology and plasticity of residual disease after neoadjuvant treatment [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 ES11-1.
Abstract ES12-3: Clinically relevant biomarkers of PARP1 inhibitor resistance and indicators of targeted combinatorial treatments
Authors: Serra V
Published: March 2020

Tumors with defective DNA repair by the homologous recombination repair (HRR) pathway are exquisitely sensitive to DNA damaging agents and to novel agents that block parallel pathways, including PARP inhibitors (PARPi). PARPi have been approved for the treatment of metastatic ovarian cancer (OvC) or breast cancer (BC). Currently used selection biomarkers to enrich the population of patients (pt) most likely to respond, namely the platinum-sensitive or BRCA1/2-mutated patients (pts), have limited predictive capacity. There is a need for more specific biomarkers to guide personalized treatment. Genomic scars/signatures have been proposed as putative biomarkers associated with DNA repair deficiency. A major limitation of these assays is the lack of specificity in HRR-altered tumors once they have restored the HRR function as mechanism of drug resistance. Functional assays are therefore needed to assess the actual status of tumor HRR, both in BRCA1/2-mutated pts and in BRCA1/2-wt, to identify tumors with germline/somatic HRR deficiency that could benefit of PARPi treatment. In this sense, the RAD51 foci assay is a functional and dynamic biomarker of HRR that correlates with PARPi response. In this educational talk, we will review the current knowledge on PARPi sensitivity and resistance in breast cancer, response biomarkers and the potential of targeting the replication stress response to revert PARPi resistance, namely using WEE1 or ATR inhibitors (WEE1i, ATRi). Our preclinical work using patient-derived tumor xenoimplant models (PDX) from triple negative breast cancer (TNBC) identified selection biomarkers for WEE1i or ATRi as single agents or in combination with PARP1/2 inhibitors, and highlights the potential of DNA damage repair inhibitors for the treatment of TNBC, an approach currently being tested in the clinic.

Citation Format: V Serra. Clinically relevant biomarkers of PARP1 inhibitor resistance and indicators of targeted combinatorial treatments [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 ES12-3.
Abstract ES6-2: Alternative practical models for genetic services in the era of increased demand
Authors: Arun BAA
Published: March 2020

Despite known treatment and prevention benefits, studies have reported that less than 50% of individuals who would be appropriate candidates for consideration of BRCA1/2 genetic testing actually are referred and undergo testing. Many mutations remain undetected leading to suboptimal recommendations regarding screening for patients. Furthermore, as a consequence, at-risk family members do not undergo predictive (“cascade”) testing. There are several potential strategies to identify individuals for genetic referrals and increase testing. One important approach is the increase awareness amongst healthcare providers. The 2019 USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Using different and/or simplified screening tools in breast imaging settings for example have shown to be feasible in identifying such individuals. Studies implementing this approach in other primary care settings are ongoing. The next step in increasing genetic testing include identification of new strategies for genetic counseling and testing. Traditionally, genetic counseling has been delivered in in-person visits with the genetic counselor. However, genetic testing has become more complex due to expanding testing indications and the addition of multiple genes in testing panels. To respond to this increasing demand, new delivery models are now being implemented; such as using technology for remote genetic counseling, such as telegentic counseling, web-based counseling, or pre test video counseling (without genetic counselor) followed by back-end genetic counseling with a counselor for mutation positive individuals. Further studies are needed to understand optimal process flow in different clinical settings.

Citation Format: BAA Arun. Alternative practical models for genetic services in the era of increased demand [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 ES6-2.
Abstract ES7-1: Progression of Disease and End of life: How to Break Bad News
Authors: Winer E
Published: March 2020

As an oncologist, one of the challenges that we all face is breaking bad news to patients and families. We all face difficult conversations on a daily basis which include discussions about disease recurrence, disease progression, and end of life issues. How we approach these conversations is of critical importance to the doctor-patient relationship and can affect the quality of life of our patients. We will discuss approaches that are more and less successful, as well as the need to individualize the approach to patients. In general, a direct conversation that involves listening, expression of empathy, and incorporates optimism is often the most successful approach.

Citation Format: E Winer. Progression of Disease and End of life: How to Break Bad News [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 ES7-1.
Abstract ES7-2: The toll on health care providers
Authors: Giordano SH
Published: March 2020

The Toll on Health Care Providers

Challenging conversation between health care provider and patients and their families can contribute to provider’s burnout. A challenging interaction for a medical professional already overstretched by the healthcare system may increase levels of stress, anxiety and anger, which in turn will affect performance and communication.

Burnout is a well-known work-related stress syndrome characterized by exhaustion, cynicism, and inefficiency. It is established that at least 50% of US physicians experience professional burnout with consequent negative impact on quality care, patient satisfaction, and overall institutional success. Cancer care professionals have experienced a drastically increase in the incidence of burnout over the past decade due to the emotionally demanding nature of their work and the ever-growing burden of administrative work. A recent Medscape report describes a burnout rate of 55% among female oncologist and 45% among male oncologist.

Both individual physician level factors and organizational level factors contribute to oncologist burnout. We will discuss common driver factors and strategies to prevent and mitigate this public health problem. Many gaps in our knowledge on physician burnout remain, but effective individual and organizational interventions are crucial for the prevention and improvement of clinician well-being and need to be incorporated into oncology care.

Citation Format: SH Giordano. The toll on health care providers [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 ES7-2.
Abstract GS3-02: Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO
Authors: Dalenc Florence , Garberis Ingrid , Filleron Thomas , Lusque Amélie , Bachelot Thomas , Arnedos Monica , Campone Mario , Sablin Marie-Paule , Bonnefoi Hervé , Jimenez Marta , Alexandra Jacquet , Andre Fabrice
Published: March 2020

Background : While treatment with anti-PDL1 improves outcome in combination with chemotherapy in patients with metastatic triple negative breast cancer, its efficacy is not explored yet in the context of maintenance therapy after chemotherapy, in a population of Her2-negative metastatic breast cancer. Methods : In SAFIR02 trial (NCT : 02299999), patients are selected to present a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. All patients underwent a biopsy of metastatic disease, followed by targeted sequencing and Oncoscan when >30% cancer cells are present on HES slides. After 6 to 8 cycles of induction chemotherapy, patients who present an actionable genomic alteration are randomized between targeted therapies and continuation of maintenance chemotherapy, and patients without actionable alterations are randomized between durvalumab (dose, schedule) for 2 years and maintenance chemotherapy. As a substudy of the SAFIR02-breast trial, the SAFIR02-IMMUNO trial has its primary endpoint, the PFS, hierarchized as the primary end-point of the core of the study. The plan was to include 190 patients in order to have 80% power using a two-sided logrank test at the 5 % level of significance to detect an improvement from 3 months to 4.76 months corresponding to an HR of 0.63. Results : 191 patients have been randomized between durvalumab and maintenance chemotherapy (190 women) until now, 45.5% TNBC and 53.4% RH+. The median age was 55 years. . 91.6% (175/191) patients were randomized on their first line of chemotherapy in metastatic setting. Median number of metastatic sites at the beginning of the chemotherapy line was 2. PDL1 staining was performed on 89 available tumor FFPE blocks using SP142 antibody. 30% (n=27/89) patients presented a PDL1 positive tumor.

PFS and OS will be presented at the conference.Conclusion : This is the first randomized trial comparing aPDL1 inhibitor to chemotherapy in the maintenance setting and to address the question of the efficacy of aPDL1i in HR+/Her2- and triple negative breast cancers.

Citation Format: Florence Dalenc, Ingrid Garberis, Thomas Filleron, Amélie Lusque, Thomas Bachelot, Monica Arnedos, Mario Campone, Marie-Paule Sablin, Hervé Bonnefoi, Marta Jimenez, Jacquet Alexandra, Fabrice Andre. Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO [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 GS3-02.
Abstract P1-02-10: Using deep residual networks for malignant and benign classification of two-dimensional Doppler breast ultrasound imaging
Authors: Shia Weichung , Chen Darren
Published: March 2020

Background: The most important issue of the overall performance of traditional CAD is effective feature extraction. However, extract a meaningful image feature is a complicated and time-consuming task. This makes fine tuning of the overall performance of traditional CAD more difficult. Currently, the deep learning was considered the most advanced technology in image classification. The main benefit of deep learning is decreasing the feature selection and classification burden of generating a transformation function set and feature of the image from the data directly. We bring up a modified deep learning algorithm in classifying the benign and malignant patients in breast ultrasound image.

Methods: There are 150 benign breast tumor patients and 120 malignant patients were enrolled from January 1, 2017 to December 31, 2018. The ultrasound images are captured at the full-view of lesion in US image by experienced physicians, and the tumor size measuring was according to the largest diameter of the tumor. The patients’ ages ranged was from 35 to 75 years, and the classification of benign or malignant were pathologically proven (either by fine needle cytology, core-needle biopsy or open biopsy). A modified deep residual network was developed and utilized to generate the US image feature for classification. The 5-fold cross-validation was used to test error percentage, mean, standard deviation and the 95% level confidence interval for the baseline algorithms. The accuracy of diagnosis was estimated using the area under the receiver operating characteristic (ROC) curve (AUC) and compared with DeLong’s non-parametric test.

Results: In this study, after using the 373 ultrasonic image dataset (all images were above BI-RADS C3, according to the report) for training and testing this modified model with 5-fold cross-validation, the AUC = 0.84 (SE = 0.81 to 0.87). The sensitivity is 77.08 and the specificity is 91.07 (p < 1x10e-5). With the accuracy as an indicator, the evaluation for classifying breast tumors in this study presents the similar performance to the subjective categories determined by physicians.

Conclusions: Comparing to the previous studies, the significant improvement of this study is the input was the full-view of the image, and waive the preprocess in tumor region selection. It decreases the human effort and make the automated computer aids diagnosis possible. By using the deep residual network, the performance of classification was not inferior previous studies. It represents the deep learning have its merits in benign and malignant classification of breast ultrasound image.

Citation Format: Weichung Shia, Darren Chen. Using deep residual networks for malignant and benign classification of two-dimensional Doppler breast ultrasound imaging [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 P1-02-10.
Abstract P1-10-15: BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy
Authors: Takada Mamoru , Kaneko Yasuhiko , Haruta Masayuki , Nagai Shigenori , Inoue Kenichi , Toduka Katsunori , Kurozumi Masafumi , Takei Hiroyuki , Ogawa Seishi , Nagashima Takeshi , Sangai Takafumi , Fujimoto Hiroshi , Sakakibara Junta , Teranaka Ryotaro
Published: March 2020

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in germinal BRCA1- or BRCA2-mutation carriers. Since tumors with the phenotype have defects in the DNA damage repair pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who underwent diagnostic core-needle biopsy and received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. They had a tumor size of T1, T2, T3, or T4, a lymph node status of N0, N1, N2, or N3, and no distant metastasis (M0) at diagnosis, and were enrolled as subjects in this study. The methylation and/or loss or UPD of BRCA1 (termed BRCA1 alterations) and the loss or UPD of BRCA2 (termed BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, out of 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P<0.001 and P<0.001) and higher percentage of TP53 alterations (the loss or UPD and/or mutations) than those without (P<0.001 and P<0.001). Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4 or ERCC1/2 in tumors, patients with additional defects in DNA damage repair genes had worse OS (P=0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.

Citation Format: Mamoru Takada, Yasuhiko Kaneko, Masayuki Haruta, Shigenori Nagai, Kenichi Inoue, Katsunori Toduka, Masafumi Kurozumi, Hiroyuki Takei, Seishi Ogawa, Takeshi Nagashima, Takafumi Sangai, Hiroshi Fujimoto, Junta Sakakibara, Ryotaro Teranaka. BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy [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 P1-10-15.
Abstract P1-10-29: Radiomics improved pre-therapeutic prediction of breast cancers insensitive to neoadjuvant chemotherapy
Authors: Zhou Xuezhi , Liu Zhenyu , Du Yang , Xiong Qianqian , Wang Kun , Tian Jie
Published: March 2020

Background: Approximately 10–35% of breast cancers were found to be insensitive to neoadjuvant chemotherapy (NAC), and approximately 5% of patients had larger tumors after NAC; in these patients, NAC failed to exhibit a therapeutic effect and instead delayed surgical treatment. Thus, it is critical to identify predictive biomarkers to enhance patient selection for NAC. Here we report a radiomic model for pre-therapeutic prediction of breast cancers insensitive to NAC.

Materials and Methods: We retrospectively enrolled 125 breast cancer patients (63 in the primary cohort and 62 in the validation cohort) who underwent magnetic resonance imaging (imaging sequence: diffusion-weighted, T2-weighted and contrast-enhanced T1-weighted) before receiving NAC. All patients received surgical resection, and Miller-Payne grading system were applied to assess the response to NAC. Grade 1-2 cases were classified as insensitive to NAC. We extracted 1941 radiomic features in the primary cohort. After feature selection, the optimal feature set was used to construct a radiomic signature using machine learning. We built a combined prediction model incorporating the radiomic signature and independent clinical risk factors using multivariable logistic regression. The performance of the combined model was assessed in the validation cohort.

Results: The radiomic signature consisting 4 features showed good performance for identifying Grade 1-2 group, yielding an area under the curve (AUC) of 0.83 (95% confidence interval: 0.647–1) in the validation cohort. A clinical model based on human epidermal growth factor receptor-2 (HER2) status and Ki67 index yielded an AUC of 0.792 (95% confidence interval: 0.668–0.916) in the validation cohort. Incorporating radiomic signature, HER2 status and Ki67 index, the combined prediction model reached a better discrimination power than the radiomic signature and clinical model, with an AUC of 0.935 (95% confidence interval, 0.848–1) in the validation cohort.

Conclusion: The combined model based on radiomics and clinical variables has a great potential in predicting drug insensitive breast cancers.

Citation Format: Xuezhi Zhou, Zhenyu Liu, Yang Du, Qianqian Xiong, Kun Wang, Jie Tian. Radiomics improved pre-therapeutic prediction of breast cancers insensitive to neoadjuvant chemotherapy [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 P1-10-29.
Abstract P1-18-06: Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular breast cancer
Authors: Kurozumi Sasagu , Green Andrew R , Ellis Ian O , Rakha Emad A , Fujii Takaaki , Shirabe Ken , Heery David , Zwart Wilbert , Oesterreich Steffi , Johnston Simon J
Published: March 2020

Invasive lobular carcinoma accounts for 10-15% of breast cancer cases and typically expresses hormone receptors. Despite this, lobular tumours respond less well to endocrine therapy, and long-term patient outcomes are inferior to those with other breast cancer subtypes. In primary lobular tumours, HER2 is rarely overexpressed due to relative infrequency of ERBB2 amplification. However, somatic mutation of ERBB2 may provide an alternative and tractable mechanism for upregulation of HER2 activity, which can be effectively targeted using a second generation HER2/EGFR tyrosine kinase inhibitor such as neratinib.

In this study we performed comparative in silico analysis of ER/PR(+), HER2(-) cases of invasive lobular (N=352) and ductal carcinoma (N=1,820) from the three largest primary breast cancer clinical datasets with somatic mutations called from next generation sequencing (TCGA, METABRIC and MSK, N=2,172). Using existing functional data from in vitro, cell line and xenograft experiments, ERBB2 mutations were stratified into known ‘oncogenic‘ or ‘uncharacterized‘ and integrated with lymph node status, tumour size and grade. The primary endpoint was overall survival as these data were available across datasets. We find that lobular tumours comprise 11% of all cases but contain 40% of the somatic mutations in ERBB2 in the dataset. The overall rate of mutated ERBB2 in lobular cases is 6% (N=21) versus 1.8% (N=32) in ductal cases (p<0.0001). Using a Cox regression model, we show that oncogenic ERBB2 mutation status independently predicts overall poor survival only in lobular cases (HR 3.6, 95% CI 1.57 - 8.26; p=0.0026). For patients with lobular disease, overall survival was significantly lower if tumours harboured oncogenic ERBB2 mutation (median 64 versus 170 months, p<0.0002). We conclude that ERBB2 mutations are enriched in ERBB2 non-amplified, ER/PR(+) lobular tumours and predict poor outcome despite use of adjuvant endocrine therapy according to standard protocols. Targeted sequencing of ERBB2 should be available for patients with lobular breast cancer and represents an actionable strategy to improve patient outcomes.

Citation Format: Sasagu Kurozumi, Andrew R Green, Ian O Ellis, Emad A Rakha, Takaaki Fujii, Ken Shirabe, David Heery, Wilbert Zwart, Steffi Oesterreich, Simon J Johnston. Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular 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 P1-18-06.
Abstract P1-18-24: Trastuzumab Emtansine (T-DM1): No radiosensitizing effect in vitro on HER2-positive breast cancer cells (study in vitro)
Authors: Mignot Fabien , Kirova Youlia , Verrelle Pierre , Teulade-Fichou Marie-Paule , Megnin-Chanet Frédérique
Published: March 2020

Purpose/Objective(s): To determine the effects of concurrent irradiation and T-DM1 on HER2-positive breast cancer cell lines.

Materials/Methods: Five human breast cancer cell lines (in vitro study) presenting various levels of HER2 expression were used to determine the potential therapeutic effect of T-DM1 combined with radiation. The toxicity of T-DM1 was assessed using CellTiter-Glo® assays and cell cycle analysis was performed by flow cytometry after BrdU incorporation. HER2 cells were irradiated at different dose levels after exposure to T-DM1. Survival fractions were determined by cell survival after 5 population doubling times.

Results: The results revealed that T-DM1 induced significant lethality due to the intracellular action of DM1 on the cell cycle with significant G2/M phase blocking. Even after a short time incubation, the potency of T-DM1 was maintained and even enhanced over time, with a higher rate of cell death. After irradiation alone, the D10 (dose required to achieve 10% cell survival) was significantly higher for high HER2-expressing cell lines than for low HER2-expressing cells, with a linearly increasing relationship. In combination with irradiation, using conditions that allow cell survival, T-DM1 does not induce a radiosensitivity, both effects are strictly additive.

Conclusion: Although intrinsic HER2 expression is a factor of radioresistance, the results indicated that T-DM1 is not a radiation-sensitizer under the experimental conditions of this study. However, further investigations are needed, in particular in vivo studies before reaching a final conclusion.

Citation Format: Fabien Mignot, Youlia Kirova, Pierre Verrelle, Marie-Paule Teulade-Fichou, Frédérique Megnin-Chanet. Trastuzumab Emtansine (T-DM1): No radiosensitizing effect in vitro on HER2-positive breast cancer cells (study in vitro) [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 P1-18-24.
Abstract P1-19-28: Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative breast cancer
Authors: Jacob Sheeba , Turner Tia H. , Yu Ann K. , Coon Colin M. , Alzubi Mohammad A. , Jakubik Charles T. , Bouck Ynes , Dozmorov Mikhail G. , Boikos Sosipatros A. , Koblinski Jennifer , Harrell Joshua C. , Benes Cyril H. , Costa Carlotta , Faber Anthony C.
Published: March 2020

Triple negative breast cancer (TNBC) confers the poorest prognosis of the major subtypes of breast cancers, and often inflicts young, African-American and Hispanic women. Steadily improving survival in other subsets of breast cancers are attributed to the implementation of effective targeted therapies, which are non-chemotherapy drugs that target a specific gene in a cancer. For instance, hormone positive BCs are treated effectively with anti-hormone targeted therapy, and HER2 amplified BCs are treated effectively with anti-HER2 targeted therapy. The CRISPR/CRISPR-associated protein-9 nuclease (Cas9) system, which enables specific gene editing to occur throughout the genome, allows for broad and unbiased discovery of new drug targets. We took advantage of this system to ask whether it may identify new druggable targets to treat TNBC and performed whole genome CRISPR/cas9 screening in two TNBC cell lines, BT549 and MDA-MB-468. To account for the heterogeneity found in TNBC, we further expanded the screen into seven other TNBC cell lines, by focusing on a select number of hits from the initial screen. This helped us identify a novel druggable target in TNBC, the ubiquitin activating enzyme 1 (UBA1). We took advantage of a recently reported small molecule inhibitor of UBA1, TAK-243, which is already in clinical trial evaluation in hematological cancers. Characterization of TAK-243 in cell culture models of TNBC and ex-vivo patient-derived xenografts (PDXs) demonstrated nanomolar IC50 toxicity, which was significantly lower than for tissue-derived normal cells. Mechanistically, TAK-243 therapy induced ER stress and the unfolded protein response in TNBC both in vitro and in vivo, leading to upregulation of activation transcription factor 4 (ATF4) and ATF6. Blocking ATF4 led to loss of NOXA and TAK-243 efficacy. TAK-243 induced tumor regressions in two PDX models of TNBC. Overall, these data demonstrate UBA1 is a novel drug target in TNBC.

Citation Format: Sheeba Jacob, Tia H. Turner, Ann K. Yu, Colin M. Coon, Mohammad A. Alzubi, Charles T. Jakubik, Ynes Bouck, Mikhail G. Dozmorov, Sosipatros A. Boikos, Jennifer Koblinski, Joshua C. Harrell, Cyril H. Benes, Carlotta Costa, Anthony C. Faber. Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative 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 P1-19-28.
Abstract P1-19-36: Exploratory analysis of TreatER+ight; a Canadian prospective real-world observational study in HR+ advanced breast cancer
Authors: Doyle Catherine , Califaretti Nadia , Ferrario Cristiano , Iqbal Nayyer , Hilton John , Vandenberg Theodore , Mates Mihaela , Glenns Vivian , Kulkarni Swati , Bains Puneet , Haftchenary Sina , Perri Sabrina , Chia Stephen
Published: March 2020

Background: TreatER+ight is the 1st prospective observational study in Canadian HR+ HER2- advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) (NCT02753686).

Methods: This exploratory analysis displays real-world evidence on baseline demographics, treatment patterns, sequencing, and method of access to therapy. More specifically this abstract focuses on treatment decisions around CDK4/6-based therapy at various lines of treatment. At data cut-off of April 1st 2019, 305 patients were enrolled from 24 sites since Mar'16 with 113 patients receiving CDK4/6is at baseline. 300 patients were evaluable for treatment analysis.

Results:

Baseline CharacteristicsOverall (n=305)CDK4/6 + ET (n=113)Median age, years (range)67 (23 - 92)67 (23-87)ECOG 0,1,2*95, 104, 1941,32, 4Post-menopausal*21468Pre/peri-menopausal*6530Therapy by disease severity at baselineVisceral (n = 196)Bone only (n = 101)CDK4/6 + ET7338ET5941mTOR + ET6421PI3K + ET01Current therapy on the study Overall (N = 300)CDK4/6 + ET113ET100mTOR + ET86 PI3K + ET1Current CDK therapy by line of treatmentAll CDK4/6 (N = 113)First line60Second line38Third line13 Fourth line2Overall treatment patterns by lineFirst-Line (n = 154)Second-Line (n = 111)Third-Line (n = 64)CDK 4/6i + ET855317ET582711mTOR + Exemestane82114Chemo31022Median duration on therapy in months1L2LCDK4/6 + ET8.87 (median follow-up of 9.6 mos)8.77 (median follow-up of 11.6 mos)*Data missing for some patients at the time of this analysis

Conclusions: The majority of patients enrolled (66.6%) are receiving combination therapy with the most common treatment being a CDK4/6-based therapy (56.5%). Of the patients receiving CDK4/6 at baseline a majority are receiving this therapy in the 1L (53.1%) and 2L (33.6%), with the median duration on therapy of respectively 8.87 and 8.77 months. For patients receiving CDK4/6 therapy in 1L, the most common 2L treatment is either endocrine therapy single agent and in certain parts of the country everolimus + exemestane. Further sequencing information will be analyzed and shared for this abstract.

Citation Format: Catherine Doyle, Nadia Califaretti, Cristiano Ferrario, Nayyer Iqbal, John Hilton, Theodore Vandenberg, Mihaela Mates, Vivian Glenns, Swati Kulkarni, Puneet Bains, Sina Haftchenary, Sabrina Perri, Stephen Chia. Exploratory analysis of TreatER+ight; a Canadian prospective real-world observational study in HR+ advanced 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 P1-19-36.