bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA22: Understanding the unique experience among Chinese immigrant breast cancer survivors
Authors: Lu Qian , Chu Qiao , Warmoth Krystal , Young Nelson , Young Lucy , Loh Alice , Wang Carol
Published: August 2020

Purpose: Little is known about the psychosocial barriers among immigrant Chinese American breast cancer survivors. The aim of the present study was to explore the psychosocial needs and challenges of Chinese American immigrant breast cancer survivors, and to develop and test culturally sensitive interventions to overcome these challenges.

Methods: Study one used the expressive writing approach to explore the experiences among Chinese immigrant breast cancer survivors. The participants were recruited through community-based organizations in Southern California, most of whom were diagnosed at Stages I and II (33% and 48%, respectively). Participants, on average, had been living in the USA for 19 years. Participants were asked to write three 20-minute essays related to their experience with breast cancer (in 3 weeks). Participants' writings were coded with line-by-line analysis, and categories and themes were generated. Study two used the expressive writing approach as an intervention among this population.

Results: Study one found that emotion suppression, perceived stigma about being a breast cancer survivor, and concerns about fulfilling multiple roles were reflected in the writings. Participants indicated their reluctance to disclose cancer diagnosis to family and friends and mentioned barriers of communicating with their husbands. Participants felt unfamiliar with the health care system and encountered language barriers. On the other hand, post-traumatic growth was also reflected in the writings. Study two found that expressive writing intervention facilitated post-traumatic growth and increased quality of life among this population.

Conclusions: Counseling services addressing concerns about stigma and communication among family members may benefit patients' adjustments. Tailor-made information in Chinese about diagnosis and treatment for breast cancer and health insurance in the USA as well as interventions to facilitate finding benefits and to reduce stress and stigma may also help patients go through the course of recovery.

Citation Format: Qian Lu, Qiao Chu, Krystal Warmoth, Nelson Young, Lucy Young, Alice Loh, Carol Wang. Understanding the unique experience among Chinese immigrant breast cancer survivors [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA22.
Abstract IA23: Engaging refugees and immigrants in breast health education
Authors: Shogan May , Saad-Harfouche Frances
Published: August 2020

Refugees and immigrants often come from countries where preventative medicine and cancer screening opportunities are neither attainable nor a priority. Often, preventative services like mammography are new concepts for immigrant and refugee women. Language barriers can decrease patients' access to services, especially for screening tests. Barriers to health screenings include cultural belief factors along with limited knowledge, racial discrimination, embarrassment, fear of the test and/or diagnosis, and lack of culturally appropriate health resources. While barriers make it difficult for refugee and immigrant women to gain access to health services, the need to provide culturally sensitive health educational programs that address these issues in a culturally sensitive way is essential to ensure a healthy life style for this population. The International Institute has over 100 years of experience in serving refugees and immigrants in many capacities and is considered a reliable resource within the local immigrant and refugee community. The Institute worked closely with Roswell Park Comprehensive Cancer Center, local community health centers, and resettlement agencies to provide culturally tailored health education programming to over 1500 refugee and immigrant women and men, and screened approximately 400 women for mammography and clinical breast exams. Additionally, the institute has educated over 1,000 local health care providers working with the immigrant and refugee population on the importance of cultural competency in order to impact their cultural sensitivity in their current medical practices. Educational programs that train health care providers in cultural competency have been shown to improve patient-provider interaction. Successful methods used in working with the immigrant and refugee population include utilizing cultural and linguistic diverse staff, proficient interpreters and translators, and partnering with community-based agencies that also serve this population. Building trust and creating personal relationships with female attendees are crucial in working with the immigrant and refugee population. Fear of the cancer test and/or diagnosis is a major barrier for most immigrant/refugee women, and to freely discuss breast health and the importance of cancer screening is a novel concern, as the word “cancer” is taboo in most cultures and is not openly discussed. This presentation will discuss strategies used to engage this diverse population and discuss lessons learned from multiple community-based educational programs on breast health among immigrant and refugee females.

Citation Format: May Shogan, Frances Saad-Harfouche. Engaging refugees and immigrants in breast health education [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA23.
Abstract IA24: Effect of migration to the US on health characteristics of the African diaspora
Authors: Ragin Camille
Published: August 2020

People of African descent have migrated to Philadelphia since the 17th century. First arriving by forced migration and then voluntary migration, the current Black population is heterogeneous, consisting of individuals of US ancestry (direct descendants of enslaved Africans in the US) and individuals of African and Caribbean ancestry (descendants or individuals who have voluntarily migrated to the US post-slavery). While Africa is the common ancestral origin of these Black subgroups, migrants' (whether newly arrived or settled) health characteristics usually differ from the health characteristics represented in their native country. Recent data from our US-based cohort of diverse Black participants (The Cancer Prevention Project of Philadelphia—CAP3) reveal distinct differences in health-related behaviors between US-born Blacks, Caribbean immigrants, and African immigrants. As length of time in the US increased, cancer screening habits, smoking, and BMI increase and suggest that as immigrants begin to assimilate with the dominant culture, they learn both positive and negative health behaviors.

Citation Format: Camille Ragin. Effect of migration to the US on health characteristics of the African diaspora [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA24.
Abstract IA25: The role of genetics and microbiomics in colorectal cancer among African American patients
Authors: Ashktorab Hassan , Brim Hassan
Published: August 2020

Colorectal cancer (CRC) is the third cause of death in the USA and genomic and microbiomic alterations play an important role in its development. Much of the underlying genomic “cancer driver” mutations and microbiomic actors in sporadic CRC are still under investigation. Here, we report the identification of distinct novel variants from CRC patients in mismatch repair (MMR) genes (MSH2, MHS3, and MSH6), and APC. We used targeted sequencing in 138 colon tissues to examine 98.8% of the targeted exons and splice junctions at a depth of sequencing that allowed for high confidence variant calling. After alignment and variant calling, we annotated the variants with information from the 1000 Genomes Project, COSMIC, Polyphen2, and PFAM domain and transcription factor motifs. Excluding synonymous SNVs, 212 deleterious variants in adenoma, 760 in advanced adenoma, and 2624 variants in tumors were detected. Novel variants (1591 and 1363) were found in MMR genes (MSH6 and MSH3) and APC gene, respectively. We also evaluated the utility of fecal bacterial marker candidates identified by our metagenomic analysis for CRC diagnosis. We identified Fusobacterium nucleatum as a major marker when comparing cancer vs. matched normal tissue and adenoma patients' stools vs. healthy subjects' stools. We also identified a novel bacterium Streptococcus sp. VT_162 with high diagnostic value in stool samples of preneoplastic patients. In vitro experiments showed that this bacterium promotes several carcinogenic pathways and downregulates apoptotic functions. This bacterium's diagnostic value was validated in an independent CRC cohort. Together our findings highlight the relevance of APC gene in CRC onset but also the potential underestimation of the MSI-H phenotype, especially the one associating with MSH3 alterations that correlate with poor prognosis. Many of the so-called “uncertain significance” novel mutations in MMR genes detected here were of a deleterious nature with potential therapeutic impact. Functional analysis of the novel gene targets is needed to confirm their roles in associated carcinogenic pathways. The role of immune markers is an important player in MMR defective tumors (MSI) as a result of neoantigen formation and in response to microbiomic alterations. These findings might facilitate noninvasive screening for CRC.

Citation Format: Hassan Ashktorab, Hassan Brim. The role of genetics and microbiomics in colorectal cancer among African American patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA25.
Abstract IA27: Exploring the impact of African ancestry in tumor immune response, a possible role in disparate clinical outcomes
Authors: Davis Melissa B. , Jenkins Brittany D. , Martini Rachel A. , Ali Haythem , Yates Clayton C. , Howerth Elizabeth A. , Nikolinakos Petros , Monteil Michele , Newman Lisa A.
Published: August 2020

Disparities in breast cancer survival among ethnic groups have been a persistent finding over the past five decades, exacerbated in part by the lack of improvement to non-white patient outcomes, despite treatment advancements that have improved clinical outcomes in white women. A significant part of this disparity is health equity; however, recent evidence from several groups indicates that histologic and pathologic diversity in tumor phenotypes among ethnic groups is also a key factor affecting the differences in clinical outcome. Specifically, correlated findings among women with significant West African ancestry reveal that there is a genetic link between women across the African Diaspora that is associated with aggressive tumor phenotypes, including triple-negative breast cancer. Aside from the global incidence of TNBC being higher in regions with relatively higher numbers of women with African ancestry, we also find that pathologic progression of tumors in African Americans tends to mimic that of African women. Tumor progression is directly related to the immune response elicited by the onset of tumor growth as well as the underlying tissue microenvironment, particularly the inflammatory status. We have identified several lines of evidence that suggest there is a distinct immune response to breast cancer, which is also tumor phenotype/subtype specific, when comparing patients of significant African ancestry with those of primarily European ancestry. These findings suggest that there could be a unique mechanism of tumor immunology at work, driven by population private genetic alleles derived in Africa and transmitted throughout the African Diaspora, causing a unique tumor phenotype in these breast cancer patients. This unique phenotype is likely the key factor in distinct treatment responses that result in poorer clinical outcomes for African American women.

Citation Format: Melissa B. Davis, Brittany D. Jenkins, Rachel A. Martini, Haythem Ali, Clayton C. Yates, Elizabeth A. Howerth, Petros Nikolinakos, Michele Monteil, Lisa A. Newman. Exploring the impact of African ancestry in tumor immune response, a possible role in disparate clinical outcomes [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA27.
Abstract IA47: Disparities in access and outcomes: Actions and consequences
Authors: Wong Sandra L.
Published: August 2020

Disparities in cancer care quality and outcomes are well documented, and an increasing evidence base informs a deeper understanding of the complex determinants of such disparities and their interactions. However, because the interactions are incompletely understood, work to achieve equity in cancer care has not demonstrated the desired impact in eliminating, or even meaningfully reducing, disparities at the population level. Current strategies to reduce health care disparities must take the value proposition into account, balancing the tenets of payment reform with improvements in access and quality. Coordinating the actions of policymakers and providers (including health systems and front-line clinical teams) is critical in making intentional forward progress. The impact of well-intended policies is often difficult to anticipate. This talk will highlight examples of policies and trends in health care delivery with unintended consequences on the very cancer outcomes they were meant to improve.

Citation Format: Sandra L. Wong. Disparities in access and outcomes: Actions and consequences [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA47.
Abstract IA52: Tools for assessing social determinants of health
Authors: Gomez Scarlett Lin
Published: August 2020

In 2017, AACR, ASCO, ACS, and NCI published a statement stemming from a think tank on the future of research in cancer health disparities. This statement, published in several leading oncology journals, offered recommendations in five areas for advancing cancer health disparities research. This presentation will review the recommendations for the area “defining measures and tools for the next generation of cancer health disparities research,” describe efforts to standardize data collection for social determinants of health, and explore emerging methodologic challenges in the measurement of social determinants in cancer health disparities research.

Citation Format: Scarlett Lin Gomez. Tools for assessing social determinants of health [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA52.
Abstract 03: Model regularization and considerations: Tuning dynamic borrowing in a hybrid clinical trial under Bayesian and frequentist framework
Authors: Li Ruilin , Zhu Jiawen , Fridlyand Jane
Published: August 2020

There has been growing interest in leveraging existing external control data to facilitate clinical trial inferences and decision making. In recent years, the quality of real-world data (RWD) improved significantly, allowing it to be considered for being used as an external control. Borrowing by directly pooling from such external controls to underpowered randomized study has a potential to lead to biased estimates, and a dynamic borrowing framework is recommended to better control false positive outcomes (Lewis et al., 2019). However, the parameter tuning of Bayesian methods of dynamic borrowing remains challenging in order to optimize trial operating characteristics. To provide a general guidance on prior selection and parameter tuning, we implemented and evaluated multiple popular Bayesian prior settings through computational simulations and provided a described relationship to the corresponding frequentist model with regularization. Recommended prior distribution characteristics and practical considerations are proposed.

Note: This abstract was not presented at the conference.

Citation Format: Ruilin Li, Jiawen Zhu, Jane Fridlyand. Model regularization and considerations: Tuning dynamic borrowing in a hybrid clinical trial under Bayesian and frequentist framework [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 03.
Abstract 04: Precise recruitment for precision oncology: RWD use for feasibility and patient identification
Authors: Gowrisankar Sivakumar , Qu Angela
Published: August 2020

Mesenchymal-epithelial transition (MET), that encodes c-MET receptor, is a proto-oncogene tyrosine kinase that is involved in a variety of cell-signaling pathways. In normal cells, MET is activated by hepatocyte growth factor (HGF) and is involved in the control of tissue homeostasis. In cancer cells, abnormal MET signaling is associated with angiogenesis and progression. Several activating mutations, including MET gene amplification, overexpression, exon 14 skipping, and fusions, have been associated with several cancers including non-small cell lung cancer (NSCLC), colorectal, gastric, and head and neck cancers. In addition, MET amplification is often seen in NSCLC patients with acquired resistance to EGFR inhibitors. Many small molecules and antibodies, such as cabozantinib, tepotinib, and onartuzumab, have been designed to inhibit c-MET and other tyrosine kinases. Many of these drugs only work for a subset of patients with very specific mutations. Finding the right patient for the right drug is one of the biggest challenges facing precision oncology trials. Traditionally, drug companies often would need to go with empirical information, choosing sites that were highly likely to care for patients who might harbor specific mutations and be able to participate in the clinical trials. This often means screening patients for specific MET mutations, with a high chance of failure rate in recruitment. Real-world evidence (RWE) and real-world data (RWD) are emerging areas with primary mandates to repurpose health care data generated in the real world. Specifically for oncology, RWE/RWD has been instrumental in finding the right treatment pathway for patients, identifying novel biomarkers for diseases, finding comorbidities, and identifying patients who are most likely to benefit from experimental drugs. In this presentation we will describe our RWD-based approach to identify patients with MET amplification or exon 14 skipping across cancer types, along with their site or location information. More specifically, we leverage RWD sources with access to records of patients who have consented to share their relevant information. These sources include genomic molecular profiling labs, electronic health records, and data from historical trial sites, with records linked using various integration techniques. We will present our findings with preliminary data, describe the data sources used, outline the technologies leveraged, and conclude with lessons learned.

Citation Format: Sivakumar Gowrisankar, Angela Qu. Precise recruitment for precision oncology: RWD use for feasibility and patient identification [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 04.
Abstract 14: Computer-aided discovery of small-molecule inhibitors targeting neural transcription factor BRN2 in neuroendocrine prostate tumors
Authors: Munuganti Ravi , Thaper Daksh , Aguda Adeleke , Kim Soojin , Sivak Olena , Zoubeidi Amina
Published: August 2020

Therapies targeting tumor-fueling androgens have been mainstay treatments of advanced prostate cancer for almost 5 decades. While the androgen receptor (AR) inhibitor enzalutamide (ENZ) prolongs survival of castration-resistant prostate cancer patients (CRPC), ENZ-resistant (ENZR) tumors rapidly recur. Our laboratory has identified that ENZ resistance can occur both in the presence and absence of continued classical AR activity. Lack of AR activity is clinically relevant, as it has been estimated that up to 25% of men who die from advanced CRPC have non-AR driven disease and lethal AR inactive neuroendocrine and anaplastic phenotypes of CRPC emerge after hormone therapy. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of neuroendocrine prostate cancer (NEPC). Hence, using the integrated power of computational drug discovery platform and biologic testing, we identified first-in-field inhibitors for BRN2. First, a homology model of BRN2 protein was generated and used as an input to perform large-scale virtual screening and virtual hits were tested in a series of experiments. Cpd 18-14, a lead BRN2 inhibitor, exhibited profound inhibition of BRN2 in transcriptional assay and binding to the BRN2 in cellular and in vitro assays. Furthermore, Cpd18-14 reduced the expression of neuroendocrine genes SOX2 and NCAM1. Importantly, Cpd18-14 displayed antiproliferative activity specifically in patient-derived BRN2hi NCI-H660 and in house-developed 42DENZRcells while displaying no effect on BRN2low 16DCRPC and LNCaP cells. Further, the most stable binding orientation of Cpd18-14 was determined using molecular dynamics simulations and was used to carry out structure-based lead optimization. As a result, we developed several synthetic derivatives with significant improvement in antiproliferative activity and metabolic stability. Finally, Cpd18-94 reduced the growth of NCI-H660 and 42DENZR NEPC tumors significantly in xenograft models. We anticipate that the developed drug prototypes will lay a foundation for the development of small-molecule therapies capable of combating highly aggressive and lethal form of neuroendocrine tumors.

Citation Format: Ravi Munuganti, Daksh Thaper, Adeleke Aguda, Soojin Kim, Olena Sivak, Amina Zoubeidi. Computer-aided discovery of small-molecule inhibitors targeting neural transcription factor BRN2 in neuroendocrine prostate tumors [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 14.
Abstract 32: Data-driven inference of crosstalk in the tumor microenvironment
Authors: Ghoshdastider Umesh , Naeini Marjan , Rohatgi Neha , Solai Sundar , Nguyen Tin , Revkov Egor , Skanderup Anders
Published: August 2020

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumorigenesis, yet challenging to decipher from tumor transcriptomes. Here, we report an unbiased, data-driven approach to deconvolute bulk tumor transcriptomes and predict crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. Our approach recovers known transcriptional hallmarks of cancer and stromal cells and is concordant with single-cell and immunohistochemistry data, underlining its robustness. Pan-cancer analysis reveals previously unrecognized features of cancer-stromal crosstalk. We find that autocrine cancer cell crosstalk varied between tissues but often converged on known cancer signaling pathways. In contrast, many stromal crosstalk interactions were highly conserved across tumor types. Interestingly, the immune checkpoint ligand PD-L1 was overexpressed in stromal rather than cancer cells across all tumor types. Moreover, we predicted and experimentally validated aberrant ligand and receptor expression in cancer cells of basal and luminal breast cancer, respectively. Collectively, our findings validate a data-driven method for tumor transcriptome deconvolution and establish a new resource for hypothesis generation and downstream functional interrogation of the TME in tumorigenesis and disease progression.

Citation Format: Umesh Ghoshdastider, Marjan Naeini, Neha Rohatgi, Sundar Solai, Tin Nguyen, Egor Revkov, Anders Skanderup. Data-driven inference of crosstalk in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 32.
Abstract 37: Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model
Authors: McFall Thomas , Stites Edward C.
Published: August 2020

Controversially, KRAS G13D colorectal cancer patients have been reported to benefit from treatment with the EGFR inhibitor cetuximab. That EGFR inhibitors could somehow reduce signaling through a constitutively active KRAS mutant has been taken as inconsistent with known mechanisms of RAS biology. Through a combination of computational modeling and experimentation, we recently demonstrated that EGFR inhibition results in a reduction of wild-type (HRAS and NRAS) signaling in KRAS G13D colon cancer cells, but not in colon cancer cells with the other common KRAS mutants, G12D and G12V. We demonstrated this in multiple colon cancer cell lines, and we developed the hypothesis originally from our mathematical model of oncogenic RAS signal regulation adapted to biochemical rate constants for the KRAS G13D mutant. Here, we develop and analyze an alternatively parameterized version of the computational model. Analysis of this alternative model similarly suggests that EGFR inhibition causes a greater reduction of wild-type RAS signal in KRAS G13D cancers. This further substantiates our findings, analogous to demonstration in an additional cell line or an additional mouse model. In addition to reinforcing our proposed mechanism, this work also further demonstrates the power of mechanism-based computational models of protein network biochemistry in personalized cancer medicine.

Note: This abstract was not presented at the conference.

Citation Format: Thomas McFall, Edward C. Stites. Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 37.
Abstract 38: Molecular determinants of drug response in TNBC cell lines
Authors: Merrill Nathan M. , Lachacz Eric J. , Vandecan Nathalie M. , Ulintz Peter J. , Bao Li Wei , Lloyd John P. , Morikawa Aki , Merajver Sofia D. , Soellner Matthew B.
Published: August 2020

Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. TNBC constitutes approximately 10-20% of total breast cancer cases in the US; however, TNBC tends to be more aggressive, higher grade, and have a poorer prognosis than other forms of breast cancer. While oncogenic aberrations have been identified in TNBC, such as the PI3K/AKT/mTOR pathway that is misregulated in ~25% of tumors, there is a general lack of predictive markers of therapeutic efficacy to identify subsets of patients most likely to positively respond to a given targeted or conventional therapy. Simply relying on mutation status is undependable, as some patients without PI3K mutations respond to PI3K inhibitors and some patients with PI3K mutations do not respond. Thus, there is a critical need for biomarkers of drug efficacy in TNBC to help design precision medicine clinical trials based on systematically derived predictive biomarkers. To fill this gap, we devised a strategy to identify biomarkers of drug efficacy in TNBC. Using 23 TNBC cell lines, drug sensitivity scores (DSS3) were determined across a panel of investigational drugs and drugs approved for other indications. Molecular readouts were generated for each cell line using RNA sequencing, RNA targeted panels, DNA sequencing, and functional proteomics. DSS3 values were correlated with molecular readouts using an FDR-corrected significance cutoff of p* < 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy. Molecular determinant panels were obtained from 12 drugs that were prioritized on the basis of their efficacy. Six molecular determinant panels were obtained by correlating DSS3 with molecular readouts. We found that coinhibiting correlated pathways led to robust synergy across many cell lines. Together, our work presents an integrated method to identify biomarkers of drug efficacy in TNBC, where DNA predictions correlate poorly with drug response. Furthermore, we outline a framework to identify optimal companion drugs for combination therapy.

Citation Format: Nathan M. Merrill, Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, Li Wei Bao, John P. Lloyd, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner. Molecular determinants of drug response in TNBC cell lines [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 38.
Abstract 43: Clinical implications of real-world data on plasma circulating tumor DNA in gynecologic cancer patients
Authors: Charo Lindsey Michelle , Eskander Ramez N. , Okamura Ryosuke , Patel Sandip , Nikanjam Mina , Layman Richard , Piccioni David E. , Kato Shamei , McHale Michael , Kurzrock Razelle
Published: August 2020

Molecular characterization of individual cancers is increasingly important in dictating prognostic factors and directing therapy. Next-generation sequencing of blood-derived circulating tumor DNA (ctDNA) offers less invasive, more convenient collection and a more real-time representation of a tumor and its molecular heterogeneity than tissue-based analysis. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We report the clinicopathologic and genomic information for 105 gynecologic cancer patients with ctDNA analysis, including 78 patients with tissue-based sequencing, who were enrolled in Profile Related Evidence Determining Individualized Cancer Therapy (PREDICT, NCT02478931). Tumors in our cohort included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvar or vaginal (2.9%), and gynecologic cancer of unknown primary (1.9%). The majority of patients (74.3%) had at least one characterized alteration on ctDNA analysis. The most common alterations were in the following genes: TP53 (N=59, 56.2% of patients), PIK3CA (N=26, 24.8%), KRAS (N=14, 13.3%), BRAF (N=10, 9.5%), ERBB2 (N=8, 7.6%), and MYC (N=8, 7.6%). Higher total percentage of ctDNA was associated with worse overall survival (HR 2.18, p=0.008), and therapy matched to ctDNA genomic alterations (N = 33 patients) independently predicted improved overall survival (HR 0.34, p=0.007) as compared to unmatched therapy (N = 28 patients). Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.

Citation Format: Lindsey Michelle Charo, Ramez N. Eskander, Ryosuke Okamura, Sandip Patel, Mina Nikanjam, Richard Layman, David E. Piccioni, Shamei Kato, Michael McHale, Razelle Kurzrock. Clinical implications of real-world data on plasma circulating tumor DNA in gynecologic cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 43.
Abstract IA23: ctDNA as predictive biomarkers for response and toxicity with immunotherapy
Authors: Siu Lillian L.
Published: August 2020

Immune checkpoint blockade (ICB) with anti-PD1/PD-L1 antibodies provides clinical benefit to a subset of cancer patients. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor (ct)DNA testing may perform as a predictive biomarker in patients receiving immune checkpoint blockade. In an investigator-initiated phase II study of the anti-PD1 antibody pembrolizumab in patients with advanced solid tumors (INSPIRE; NCT02644369), we collected plasma samples at baseline and prior to every third cycle. These samples were retrospectively analyzed using a validated patient-specific, amplicon-based sequencing assay to detect and quantify ctDNA levels at each plasma time point. In total, 94 patients with serial ctDNA collections in five cohorts of solid tumors received single-agent pembrolizumab 200 mg IV ever 3 weeks. Levels of ctDNA at serial time points and the change from baseline were correlated with overall survival (OS), progression-free survival (PFS), objective response rate (ORR by RECIST v1.1), and clinical benefit rate (CBR, CR + PR + SD > 6 cycles). Response was measured by RECIST v1.1. Across the five cancer cohorts, median number of pembrolizumab cycles received was 3 and median follow-up was 13.8 months. Baseline ctDNA concentration correlated with multiple efficacy measures. This association became stronger across the cohorts when considering ctDNA kinetics after treatment initiation. An early reduction in ctDNA levels (at about 6-7 weeks) was strongly correlated with OS, PFS, ORR, and CBR. Sustained ctDNA clearance during treatment preceded durable clinical response. Strikingly, all 14 patients with ctDNA clearance during treatment were alive with a median of 27.5 months follow-up. These results demonstrate the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB for advanced solid tumors of diverse histologies. Limited by the number of patients with grade 2 or higher immune-related adverse events (irAEs, 23/94 patients, 24%), no correlation was seen between irAE and cell-free DNA levels in the INSPIRE cohort. Currently we are planning interventional ICB studies using early ctDNA dynamics as predictive biomarkers.

Citation Format: Lillian L. Siu. ctDNA as predictive biomarkers for response and toxicity with immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr IA23.
Quantitative Analysis of Perfusion Characteristics Using Contrast-Enhanced Ultrasound in Patients with Choroidal Metastasis
Authors: Li Dongjun , Wang Ziyang , Chen Wei , Zhao Qi , Li Yifeng , Cui Rui , Shen Lin , Liu Qian , Cao Kai , Liu Yueming , Wei Wenbin , Yang Wenli
Published: August 2020

Purpose: The aim of the study was to quantitatively analyze the perfusion characteristics of choroidal metastasis using contrast-enhanced ultrasound (CEUS) and compare its perfusion characteristics with these of choroidal hemangioma and choroidal melanoma. Methods: The patients who were clinically diagnosed with choroidal metastasis were classified as the study group, and the patients who were diagnosed with choroidal hemangioma and choroidal melanoma during the same period were classified as the comparison group. All patients underwent CEUS examination, and Sonoliver was used to obtain the data on quantitative parameters of the tumor and the adjacent normal orbital tissues, including maximum of intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (mTT). Wilcoxon signed rank test was performed to compare the quantitative parameters of choroidal metastasis and normal orbital tissues. Kruskal-Wallis test was adopted to compare the quantitative parameters of the 3 types of tumors, and Bonferroni was used to correct the results of the multiple comparisons. Receiver operating characteristic (ROC) curve analysis was used to identify valuable parameters. Results: Twenty-six patients (26 eyes) with choroidal metastasis, 55 patients (55 eyes) with choroidal hemangioma, and 49 patients (49 eyes) with choroidal melanoma were enrolled in this study. The IMAX of choroidal metastasis was significantly higher than that of normal orbital tissues, while RT, TTP, and mTT were significantly shorter than these of normal orbital tissues (all p values were <0.001). The IMAX of choroidal metastasis was lower than that of choroidal hemangioma, and RT, TTP, and mTT were shorter than these of choroidal hemangioma and choroidal melanoma (p = 0.002, p = 0.004, p = 0.007). ROC curve analysis showed that areas under the ROC curves (AUCs) of RT and mTT (AUC = 0.851, 95% CI 0.783–0.918 and 0.849, 95% CI 0.783–0.915) were larger. Conclusion: Quantitative analysis with CEUS can reflect the perfusion characteristics of choroidal metastasis and can exhibit the difference between its perfusion characteristics and these of choroidal hemangioma and choroidal melanoma. RT and mTT may serve as useful parameters for differentiating choroidal metastasis from choroidal hemangioma and choroidal melanoma.
Asthma Promotes Choroidal Neovascularization via the Transforming Growth Factor Beta1/Smad Signalling Pathway in a Mouse Model
Authors: Yang Fei , Sun Yaoyao , Bai Yujing , Li Shanshan , Huang Lvzhen , Li Xiaoxin
Published: August 2020

Introduction: The association between age-related macular degeneration and asthma is controversial. Transforming growth factor beta (TGF-β), which plays a critical role in asthma, has been extensively studied with regard to its function in choroidal neovascularization (CNV). In the present study, we aimed to investigate the role of TGF-β and the possible mechanism of CNV formation complicated with asthma and to explore the effect of a TGF-β inhibitor on CNV development in asthma mouse models. Methods: Laser-induced CNV and ovalbumin-induced asthma mouse models were divided into 5 groups: control group, acute asthma group, chronic asthma group, inhibitor-treated acute asthma group, and inhibitor-treated chronic asthma group. The gene expression patterns of angiogenic cytokines, vascular endothelial growth factor (VEGF) receptors and inflammasomes in the control group, acute asthma group, and chronic asthma group were detected using a QuantiGene Plex 6.0 Reagent System. Fundus fluorescein angiography and histology of CNV lesions stained with haematoxylin-eosin were performed to evaluate CNV formation. Quantitative real-time PCR and western blotting were used to assess TGF-β1, TGF-β2, and VEGF expression and Smad2/3, AKT, p38 MAPK, and ERK1/2 signal transduction and phosphorylation in retinal and choroidal tissues from each group. Results: In this study, we verified that laser treatment led to more CNV and vascular leakage in asthmatic mice than that in control mice. The changes were particularly notable in the chronic asthma group. The respective TGF-β1, VEGF, and phosphorylated Smad2/3 (p-Smad2/3) mRNA and protein levels in retinal and choroidal tissues were significantly upregulated in both the acute and chronic asthma groups. After injection of a TGF-β inhibitor, a distinct decline in VEGF, TGF-β1, and p-Smad2/3 protein and mRNA levels was observed, and the mean CNV area also decreased. Conclusion: We provide new evidence that asthma could be a risk factor for CNV development via the TGF-β1/Smad signalling pathway. A TGF-β inhibitor can be applied as a useful, adjunctive therapeutic strategy for preventing CNV formation in asthmatic patients.
Polar wolf optimization algorithm for solving optimal reactive power problem
Authors: Lenin Kanagasabai
Published: August 2020

This paper proposes polar wolf optimization (PWO) algorithm to solve the optimal reactive power problem. Proposed algorithm enthused from actions of polar wolves. Leader’s wolves which denoted as xα are accountable for taking judgment on hunting, resting place, time to awaken etc. second level is xβ those acts when there is need of substitute in first case. Then xγ be as final level of the wolves. In the modeling social hierarchy is developed to discover the most excellent solutions acquired so far. Then the encircling method is used to describe circle-shaped vicinity around every candidate solutions. In order to agents work in a binary space, the position modernized accordingly. Proposed PWO algorithm has been tested in standard IEEE 14, 30, 57,118,300 bus test systems and simulation results show the projected algorithms reduced the real power loss considerably.
Power system fault identification and localization using multiple linear regression of principal component distance indices
Authors: Mukherjee Alok , Kundu Palash Kr. , Das Arabinda
Published: August 2020

This paper is focused on the application of principal component analysis (PCA) to classify and localize power system faults in a three phase, radial, long transmission line using receiving end line currents taken almost at the midpoint of the line length. The PCA scores are analyzed to compute principal component distance index (PCDI) which is further analyzed using a ratio based analysis to develop ratio index matrix (R) and ratio error matrix (RE) and ratio error index (REI) which are used to develop a fault classifier, which produces a 100% correct prediction. The later part of the paper deals with the development of a fault localizer using the same PCDI corresponding to six intermediate training locations, which are analyzed with tool like Multiple Linear Regression (MLR) in order to predict the fault location with significantly high accuracy of only 87 m for a 150 km long radial transmission line.
Stable and robust control strategy using interval-valued fuzzy systems
Authors: Bounouara Nadia , Ghanai Mouna , Medjghou Ali , Chafaa Kheireddine
Published: August 2020

In this paper we propose an adaptive interval valued fuzzy controller for high performance direct vector-controlled induction motor drive. Interval valued controller compared with type-1 fuzzy controller has the advantage that it

can take into account the linguistic uncertainties present in the rules of the estimated models. The proposed control framework consists of a mixture of two controllers: an interval valued fuzzy controller and a supervisory controller. The supervisory controller is used when the system starts to become unstable. The free parameters for the proposed controller are changed according to some learning rules based on Lyapunov stability. Simulation results on an induction motor show the effectiveness of the introduced method.
Power loss reduction by chaotic based predator-prey brain storm optimization algorithm
Authors: Lenin Kanagasabai
Published: August 2020

In this paper chaotic predator-prey brain storm optimization (CPB) algorithm is proposed to solve optimal reactive power problem. In this work predator-prey brain storm optimization position cluster centers to perform as predators, consequently it will move towards better and better positions, while the remaining ideas perform as preys; hence get away from their adjacent predators. In the projected CPB algorithm chaotic theory has been applied in the modeling of the algorithm. In the proposed algorithm main properties of chaotic such as ergodicity and irregularity used to make the algorithm to jump out of the local optimum as well as to determine optimal parameters CPB algorithm has been tested in standard IEEE 57 bus test system and simulation results show the projected algorithm reduced the real power loss considerably.
Performance evaluation and load demand management of grid connected hybrid wind-solar-battery system
Authors: Venkatachalam K. M. , Saravanan V.
Published: August 2020

In this paper, Performance of the grid connected hybrid wind-solar energy

system and load demand response of the battery integrated single phase voltage source inverter is presented. The wind energy conversion system is

generating AC power and the solar PV system is generating DC power and

both are integrating with battery in the common DC bus. The output voltage

of the wind and solar system are controlling using dc-dc converters and it

achieved more than the battery voltage. P&O algorithm used MPPT based

voltage controller is driving the dc-dc converter with a reference voltage

value of the battery. The single-phase full-bridge converter is converting DC

to AC power and feeding into the standalone AC loads and distribution grid

with IEEE 519 standard. The bi-directional converter is controlling the directions of power flow and it operates two modes namely inverter mode and rectifier mode based on a voltage level of the battery. In this bi-directional converter is controlling by the PI controller with the reference value of the DC bus voltage and load current. The power quality and demand response of the inverter is observing at various types of load conditions in standalone mode and grid-connected mode using experimental results.
Diminution of factual power loss by enhanced bacterial foraging optimization algorithm
Authors: Lenin Kanagasabai
Published: August 2020

This paper presents an enhanced bacterial foraging optimization (EBFO) algorithm for solving the optimal reactive power problem. Bacterial foraging optimization is based on foraging behaviour of Escherichia coli bacteria which present in the human intestine. Bacteria have inclination to congregate the nutrient-rich areas by an action called as Chemo taxis. The bacterial foraging process consists of four chronological methods i.e. chemo taxis, swarming and reproduction and elimination-dispersal. In this work rotation angle adaptively and incessantly modernized, which augment the diversity of the population and progress the global search capability. The quantum rotation gate is utilized for chemo taxis to modernize the state of chromosome projected EBFO algorithm has been tested in standard IEEE 14,300 bus test system and simulation results show the projected algorithm reduced the real power loss extensively.
Effect of renewable energy sources integration on the optimal coordination of directional over-current relays in distribution system
Authors: Bougouffa Lazhar , Chaghi Abdelaziz
Published: August 2020

The demand for power electricity is growing fast and one of the main tasks for power engineers is to generate electricity from renewable energy sources (RES).

Nevertheless, problems arise when the new generation is integrated in the power distribution network. Under this condition, the main purpose in this paper, an investigation of the effect of RES integration on the optimal coordination of directional over-current relays in distribution system, a dual simplex optimization algorithm has been presented to determine the coordination of directional over-current relays (DOCRs). The system used to check the efficiency of the optimization algorithm which is IEEE 33-bus models. The analysis is performed in MATLAB software environment.