bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-10-14: Higher radiation dose to the heart in left sided breast cancer; anatomy versus dosimetry
Authors: El-Din Mohamed Alm , Niemierko Andrzej , Taghian Alphonse 
Published: March 2023

Abstract
Abstract: Background: There is assumption that omitting the internal mammary chain radiotherapy (IMC RT) in patients with breast cancer (BC) will significantly reduce the cardiac exposure for all patients regardless the cardiac anatomy of each patient. Aim: to evaluate the impact of IMC RT on the dose received by the heart and its chambers in patients with favorable versus unfavorable cardiac anatomy. Patients and methods: CT scans were obtained of 20 patients with left-sided BC, 10 with favorable and 10 with unfavorable cardiac anatomy. Three plans were generated for each patient, one treating only the breast with tangents, and one treating the breast and IMC with wide photon tangents, and one treating the breast and IMC to 50Gy with photon tangent fields and a matching medial electron field. Dose volume histograms (DVHs) were generated for the heart and chambers. The equivalent uniform doses (EUDs) were calculated for each DVH, and the mean EUDs for plans with unfavorable and favorable cardiac anatomy were compared using a two-sided two-sample T-test Results: The mean dose received by the heart from plans with tangents plus IMC fields in patients with favorable cardiac anatomy was significantly lower than that received from plans with tangents only or wide tangents in patients with unfavorable anatomy (P &lt; .0001). The average EUD for plans with tangents and IMC fields in the favorable group was 16 Gy (SD = 4.5) as compared to 36 Gy (SD = 3.6) and 37 Gy (SD = 5.1) for plans with tangents only and wide tangents in the unfavorable group, respectively ((P &lt; .0001). The doses to the right ventricle were not significantly different. Conclusions: Ttreatment plans should be individualized based on the cardiac anatomy of each patient.
Citation Format: Mohamed Alm El-Din, Andrzej Niemierko, Alphonse Taghian. Higher radiation dose to the heart in left sided breast cancer; anatomy versus dosimetry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-14.
Abstract P1-10-15: Concious sparing of contralateral thyroid lobe in Ca Breast patients receiving post mastectomy radiotherapy by IMRT technique – A single institution dosimetric study
Authors: Chomal Manish , Iyer Minaal , Kalimurthy Ananth , Sahay Joshua , Banik Sushanta 
Published: March 2023

Abstract
Purpose/Objective(s): The purpose of this paper is to report the dosimetric effects of conscious sparing of contralateral lobe of thyroid gland in carcinoma breast patient receiving locoregional radiation by tangential beam Intensity Modulated radiotherapy technique.
Materials/Methods: Treatment plans of 20 Ca Breast patients, who received post mastectomy adjuvant locoregional radiotherapy, were evaluated. Since October 2021 we adopted a department protocol of conscious sparing of contralateral thyroid in breast radiotherapy. 10 of these had conscious sparing of contralateral thyroid (group A) whereas 10 of old plans were evaluated when C/L thyroid were not given constraints & are being passively spared due to location on contralateral/non treatment side of neck (group B). Treatment planning was done using tangential beam (6 MV) IMRT in Eclipse 13.7 TPS in all of these patients. All of these patients received treatment to chest wall & SCF. RTOG contouring guidelines were followed in all the patients. Prescription Dose was 40Gy in 15# for both groups. The best treatment plans were selected ensuring 95% PTV dose coverage and acceptable dose to OARs. Uniform contouring, plan optimization & evaluation protocols were followed for all of these patients.
Results: The mean thyroid volume in group A is 4.30cc & in group B is 3.99cc which is not statistically different (P value -0.639) The mean dose of thyroid in group A is 7.98Gy whereas in group B it is 17.00Gy which is spastically significant (P value – 0.000003). Comparison of mean dose to contralateral lobe (in Gy) between the two groups
Groups No. Mean ± SD ‘t’ value P value
Thyroid dose with constraint 10 7.98±1.46 -6.702, df=18 0.000003*
Thyroid dose without constraint 10 17.00±3.99
Unpaired ‘t’ test applied. P value = 0.000003, Significant
Conclusion: OARs present on contralateral side are passively spared due to the location. This often results in a tendency of not actively prescribing constraints to these. This study emphasizes that conscious sparing of contralateral Thyroid lobe can further reduce the dose to significant levels. This reduction can preserve thyroid function further. Further clinical trials are required to corroborate this dosimetric gain with clinical thyroid function preservation.

Citation Format: Manish Chomal, Minaal Iyer, Ananth Kalimurthy, Joshua Sahay, Sushanta Banik. Concious sparing of contralateral thyroid lobe in Ca Breast patients receiving post mastectomy radiotherapy by IMRT technique – A single institution dosimetric study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-15.
Abstract P1-11-03: VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers
Authors: Ko Yikyung , yoo Jihye , Jung Hong-ryul , Lim Hyerim , Lee YeongDeok , Kim Se Hyuk , Shin Dong Guk , Cho Serin , hoe Heo Myung , Kim Haelee , Cho Ha Yeon , Han Ah Reum , Ko Eunhwa , Choi Hwan Geun , Kim Deakwon , Kim Sunghwan 
Published: March 2023

Abstract
The brain is a common target organ for breast cancer metastasis, and the risk of brain metastasis is usually high for patients with HER2-positive breast cancer. While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration. There is still an unmet medical need for active HER2-positive BCBM. VRN101099 is a highly selective kinase inhibitor of HER2 (Eurofins scanMAX Kinase Profiling, S-score (35) of 0.01). VRN101099 has single- to double-digit nanomolar (IC50) cellular potency in HER2-dependent cancer cells, and Ba/F3 cells expressing HER2 wild type or mutations with selectivity over wildtype EGFR. VRN101099 inhibited proliferation of BT474 with 3.6 nM IC50 but HaCaT with 829.2 nM IC50. VRN101099 binds HER2 kinase by forming a covalent bond to the Cys805 and its irreversible inhibition resulted in a longer target resident time than Tucatinib, confirmed by in vitro washout experiments. Robust in vivo activity of VRN101099 was observed in HER2-positive BT474 xenograft models. Moreover, once daily oral administration of VRN101099 significantly regressed intracranial BT474 tumor, demonstrating greater efficacy than twice daily oral administration of Tucatinib. These results were well explained by the superior brain to plasma exposure of VRN101099 to Tucatinib. Also, VRN101099 showed high exposure in the target organ, the fat pad, which potentiated better clinical translation. These anti-tumor efficacies are correlated with pharmacodynamic responses, as confirmed by decreased HER2, AKT, and ERK phosphorylation. In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers.
Citation Format: Yikyung Ko, Jihye yoo, Hong-ryul Jung, Hyerim Lim, YeongDeok Lee, Se Hyuk Kim, Dong Guk Shin, Serin Cho, Myung hoe Heo, Haelee Kim, Ha Yeon Cho, Ah Reum Han, Eunhwa Ko, Hwan Geun Choi, Deakwon Kim, Sunghwan Kim. VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-03.
Abstract P1-11-06: Multi-omics profiling of HER2-low breast cancer reveals clinically relevant subgroups and therapeutic pathways
Authors: Chen Lie , Liu Cui-Cui , Ge Jing-Yu , Shao Zhi-Ming , Yu Ke-da 
Published: March 2023

Abstract
The current HER2 testing algorithm can distinguish tumors that are completely negative for HER2 (IHC 0, HER2-zero) from HER2-low tumors [low (IHC 1+) or moderate expression (IHC 2+, ISH-)]. Because HER2-zero cases have often been combined with HER2-low cases, the clinical and biological understanding of HER2-low tumors is limited. To provide complementary information and shed light on the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multi-omics study of hormone receptor (HR)-negative and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified three subgroups: basal-like (BSL), receptor tyrosine kinase relevant (TKR), and mesenchymal stem-like (MSL). These three subgroups had distinct features and potential therapeutic targets and were validated in external datasets. Interestingly, the TKR subgroup (which exists in both HR-positive and HR-negative breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment with tyrosine kinase inhibitor (Lapatinib or Tucatinib) could inhibit HER2-signaling and induce accumulated expression of nonfunctional HER2 via a feedback loop, resulting in increased sensitivity to sequential HER2-targeting antibody-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for the previously targetless HER2-low TNBC subtype.
GRAPH ABSTRACT
Highlights of characteristics of HR-negative and HER2-low breast cancer subgroups
Table S1. Highlights of characteristics of HR-negative and HER2-low breast cancer subgroups.
Citation Format: Lie Chen, Cui-Cui Liu, Jing-Yu Ge, Zhi-Ming Shao, Ke-da Yu. Multi-omics profiling of HER2-low breast cancer reveals clinically relevant subgroups and therapeutic pathways [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-06.
Abstract P1-11-16: Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study
Authors: Yin Yongmei , Li Wei , huang Xiang , Sun Chunxiao , Hua Yijia , Jin Nan , Wu Xinyu 
Published: March 2023

Abstract
Background Trastuzumab emtansine (T-DM1) has shown great effectiveness in treating HER2-positive metastatic breast cancer, but therapies subsequent to T-DM1 failure remain controversial. Here, we investigated efficacy and safety of tyrosine kinase inhibitors (TKIs) based therapy in T-DM1 resistant HER2-positive metastatic breast cancer. Methods From August 2019 to April 2022, 53 HER2-positive metastatic breast cancer patients received TKIs-based therapy after T-DM1 failure in Jiangsu Province Hospital. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles were reported. Results 53 patients received TKIs-based therapies as a second or later line therapy. 51 (96.2%) patients received a combined therapy, including TKIs plus capecitabine, vinorelbine or trastuzumab. 2 (3.7%) patients received TKIs alone. The median follow-up time was 19.7 months (95%CI 15.4-24.0). The median PFS was 11.9 months (95%CI 7.9-15.9). OS has not reached. ORR was 19.6% and CBR was 72.5%. For patients who had brain metastasis (n=12), the median PFS was 10.5 months (95%CI 7.5-13.5) and intracranial ORR was 33.3%. Compared with lapatinib (n=30), pyrotinib (n=21) provided a better PFS after T-DM1 progression (8.0 months vs. 19.0 months, P=0.033). The most common adverse events were thrombocytopenia (12, 23.6%), diarrhea (8, 15.7%), leucopenia (8, 15.7%) and hand-foot syndrome (8, 15.7%). Conclusion TKIs-based therapy could prolong the survival of HER2-positive metastatic breast cancer patients after T-DM1 failure, including those with brain metastases. Compared with lapatinib, pyrotinib might provide better outcomes for overcoming T-DM1 resistance.
Citation Format: Yongmei Yin, Wei Li, Xiang huang, Chunxiao Sun, Yijia Hua, Nan Jin, Xinyu Wu. Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-16.
Abstract P1-13-01: Targeting RRM2 for the treatment of palbociclib resistant breast cancer
Authors: Sultana Nahid , Elford Howard L. , Faridi Jesika S. 
Published: March 2023

Abstract
Hormone receptor (HR) positive breast cancer (BC) is a prevalent disease accounting for almost 2 million new cases globally. Almost 70-80% of breast cancer patients are women with a positive score for the estrogen receptor (ER). HR positive BCs of all stages are selectively treated with endocrine therapy targeting ER activity. Intrinsic and acquired resistance are common phenomena, impacting patient outcomes negatively. Palbociclib is an FDA approved checkpoint inhibitor for the treatment of HR+/HER2- breast cancer in combination with aromatase inhibitors or selective estrogen receptor degraders. However, patients responding well to the therapy in the beginning, lose sensitivity to palbociclib with time. Ribonucleotide reductase (RR) is a rate limiting enzyme in DNA synthesis consisting of two subunits RRM1 and RRM2. In our previous study, we have shown that RRM2 is upregulated in ER positive tamoxifen resistant BC. Previously, we have also reported that didox (DDX) which is a unique RRM2 enzyme inhibitor can significantly halt malignant breast cancer cell division in combination with an anthracycline drug doxorubicin by targeting RRM2, mutant p53 and NFkB regulatory proteins. In this study, we target palbociclib resistant BC with DDX to circumvent palbociclib resistance. For this purpose, we have developed palbociclib resistant ER positive MCF7 and ER negative MDA-MB-468 breast cancer cell lines. Here, we report morphological changes in parental as compared to palbociclib resistant cells after treatment with palbociclib alone, DDX alone or with palbociclib as compared to non-treated cells. Cell proliferation studies confirm the synergistic combinatorial effect of palbociclib and DDX compared to palbociclib or DDX alone. We also report that DDX alone or in combination with palbociclib downregulates cell cycle and NFkB proteins in palbociclib resistant ER positive MCF7 and ER negative MBA-MB-468 breast cancer cell lines.
Citation Format: Nahid Sultana, Howard L. Elford, Jesika S. Faridi. Targeting RRM2 for the treatment of palbociclib resistant breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-01.
Abstract P1-13-04: Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers
Authors: Boyd David , Harrell Chuck 
Published: March 2023

Abstract
Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers David C. Boyd1,2, Amy L. Olex3, Tess Leftwich1, Nicole Hairr1, Alex K. Duong1, Narmeen S. Rashid1,3, Mohammad A Alzubi1,2, Holly Byers1, Aaron D. Valentine1, Julia E. Altman1, Emily Zboril1, Jacqueline M. Grible1, Madelyn Esquivel1, Scott A. Turner1, Andrea Ferreira-Gonzalez1, Mikhail G. Dozmorov5, J. Chuck Harrell1,2,6 1Department of Pathology, Virginia Commonwealth University; 2Integrative Life Sciences Program, VCU; 3Wright Center for Clinical and Translational Research, VCU; 4Department of Biology, University of Richmond; 5Department of Biostatistics, VCU; 6Massey Cancer Center, VCU. There is an urgent need for new therapeutic options for basal-like Triple Negative Breast Cancers (TNBC). To mirror the NCI-ComboMATCH study, and identify new synergistic drug combinations, we analyzed a set of 20 breast cancer patient-derived xenografts and 14 cell lines to identify targetable targets in each model. The Oncomine Comprehensive Assay v3 was performed to assess 161 genes for hotspot mutations, focal copy number variants, amplification/deletions, and RNA-fusion genes. Next, each PDX and their isogenic drug-resistant sublines were analyzed with bulk RNA-sequencing (217 samples) and cell single-cell RNA-sequencing (~100,000 cells). Of all NCI-MATCH defined targetable mutations, 37% of the models contained pathogenic PIK3CA amplifications or mutations. PIK3CA is one of the most common oncogenic aberrations identified in patients and the PI3K pathway is overactive in the majority of TNBCs, therefore we sought to target it across all models and identify the most efficacious synergistic drug partner. Short-term cultures of each PDX model were screened with a library of &gt;1,000 FDA-approved/experimental drugs to identify compounds that were cytotoxic. Synergistic drug screens were then performed with each drug in combination with the PI3K inhibitor byl-719 (alpelisib) a current standard-of-care drug used for PI3K mutant ER+ disease. Synergism was identified using coefficient of drug interaction (CDI) calculations and 10 drugs were identified as synergistic across several models. Using several criteria, including clinical status and pathway analysis, 3 drugs were selected for CompuSyn-based synergism testing and each was confirmed to be synergistic in vitro. Testing with in vivo models of each drug combination has thus far confirmed that each is synergistic per CDI metrics. Those combinations are currently being tested for efficacy in the metastatic setting with a set of basal-like PDXs.
Citation Format: David Boyd, Chuck Harrell. Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-04.
Abstract P1-13-12: Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative breast cancer
Authors: Terrero David , Tiwari Amit , Raman Dayanidhi 
Published: March 2023

Abstract
The development of drug resistance is a primary cause of chemotherapy failure in the treatment of triple-negative breast cancer (TNBC). Some cancer cells are resistant to drugs with unrelated structures and mechanisms of action, a phenomenon known as multidrug resistance (MDR). Although taxanes such as docetaxel and paclitaxel are effective against non-metastatic and metastatic TNBC and other types of breast cancer, they eventually become ineffective due to development of drug resistance. Mitochondrial dynamics has gained significant attention as a means to treat MDR and non-MDR cancers. Mitochondrial dynamics determine the number, shape, and location of mitochondria within cells, which are fundamental to the health of the cell. Among its key components is the mitochondrial fission-promoting dynamin-related protein 1 (Drp1). There is mounting evidence indicating that both Drp1 and its phosphorylated form promote cancer survival, resistance to apoptosis, and chemoresistance. We observed increased phosphorylation of Drp1 at Ser616 as well as phosphorylation of its upstream kinase ERK1/2 in TNBC lines SUM159PT and its paclitaxel-resistant derivative that we developed called SUM159PT/PAC200 that displays more than an 80-fold increase in resistance to paclitaxel. Using CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in both lines. When Drp1 is genetically ablated, paclitaxel resistance in SUM159PT/PAC200 was significantly reversed. Furthermore, proliferation, migration, and invasion capabilities were decreased in both parental and paclitaxel-resistant Drp1 knockout lines. In SUM159PT/PAC200 Drp1-KO cells, a mesenchymal to epithelial transition (MET) was observed as indicated by downregulation of mesenchymal markers such as N-cadherin and -catenin, and upregulation of the epithelial marker ZO-1. Interestingly, Drp1 knockout halted the ability of SUM159PT/PAC200 to form colonies in soft agar. SUM159PT/PAC200 cells strongly express the MDR pump P-glycoprotein (ABCB1), to which paclitaxel is a known substrate, and genetically targeting Drp1 reduced the expression to almost undetectable levels. Taken together, these findings suggest that Drp1 is both a resistance factor and a key protein in breast cancer proliferation and dissemination, making it a promising actionable molecular target in the treatment of TNBC. Further studies are in progress to understand the role of Drp1 in the development and maintenance of MDR phenotype, proliferation, and invasion.
Citation Format: David Terrero, Amit Tiwari, Dayanidhi Raman. Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-12.
Abstract P1-13-23: Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft
Authors: Dozmorov Mikhail , Marshall Maggie , Rashid Narmeen , Grible Jacqueline , Valentine Aaron D. , Olex Amy , Murthy Kavita , Chakraborty Abhijit , Reyna Joaquin , Figueroa Daniela Salgado , Lee Da-Inn , Baur Brittany , Roy Sushmita , Ay Ferhat , Harrell Chuck 
Published: March 2023

Abstract
Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (&lt; 2Mb) interactions, chromatin looping, formation of topologically associating domains (TAD), chromatin state switching into a more active state, and amplification of ATP-binding cassette (ABC) transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.
Citation Format: Mikhail Dozmorov, Maggie Marshall, Narmeen Rashid, Jacqueline Grible, Aaron D. Valentine, Amy Olex, Kavita Murthy, Abhijit Chakraborty, Joaquin Reyna, Daniela Salgado Figueroa, Da-Inn Lee, Brittany Baur, Sushmita Roy, Ferhat Ay, Chuck Harrell. Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-23.