bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical presentation and outcomes in children with retinoblastoma managed at the Uganda Cancer Institute
Authors: Kalinaki Abubakar , Muwonge Haruna , Balagadde-Kambugu Joyce , Mulumba Yusuf , Ntende Jacob , Ssali Grace , Nakiyingi Lydia , Nakanjako Damalie , Nalukenge Caroline , Ampaire Anne M.
Published: March 2022

Background. The majority of patients with retinoblastoma, the most common intraocular cancer of childhood, are found in low-and middle-income countries (LMICs), with leukocoria being the most common initial presenting sign and indication for referral. Findings from the current study serve to augment earlier findings on the clinical presentation and outcomes of children with retinoblastoma in Uganda. Methods. This was a retrospective study in which we reviewed records of children admitted with a diagnosis of retinoblastoma at the Uganda Cancer Institute from January 2009 to February 2020. From the electronic database, using admission numbers, files were retrieved. Patient information was recorded in a data extraction tool. Results. A total of 90 retinoblastoma patients were studied, with a mean age at the first Uganda Cancer Institute (UCI) presentation of 36.7 months. There were more males (57.8%) than females, with a male to female ratio of 1.37 : 1. The majority (54.4%) had retinoblastoma treatment prior to UCI admission. The most common presenting symptoms were leukocoria (85.6%), eye reddening (64.4%), and eye swelling (63.3%). At 3 years of follow-up after index admission at UCI, 36.7% of the patients had died, 41.1% were alive, and 22.2% had been lost to follow-up. The median 3-year survival for children with retinoblastoma in our study was 2.18 years. Significant predictors of survival in the multivariate analysis were follow-up duration (P̲<0.001), features of metastatic spread (P=0.001), history of eye swelling (P=0.012), and bilateral enucleation (P=0.011). Conclusions. The majority of children who presented to the Uganda Cancer Institute were referred with advanced retinoblastoma, and there was a high mortality rate. Retinoblastoma management requires a multidisciplinary team that should include paediatric ophthalmologists, paediatric oncologists, ocular oncologists, radiation oncologists, and nurses.
Abstract ES5-3: Management of special subtypes of TNBC
Authors: Thomas A
Published: March 2022

Less common subtypes of triple-negative breast cancer encompass a heterogeneous group of cancers some of which are rare and others which are ultra-rare. Given the high prevalence of breast cancer, less common TNBC subtypes can be encountered with some frequency in clinical practice. These subtypes, which include, metaplastic, medullary, apocrine, mucoepidermoid, secretory, and adenoid cystic breast cancer, have diverse histologies, molecular profiles, and prognoses. This educational discussion will review the distinct features of less common triple-negative breast cancers and will address how these impact current, as well as possible future, management strategies. Possible clinical trial approaches to further understand and better treat special subtypes of TNBC will also be discussed.

Citation Format: A Thomas. Management of special subtypes of TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES5-3.
Abstract P1-02-15: Predicting molecular subtypes of breast cancer using
Authors: Huang Chi-Cheng , Phan Nam Nhut , Tseng Ling-Ming
Published: March 2022

Purpose: Breast cancer is a heterogeneously complex disease. A number of molecular subtypes with distinct biological features lead to different treatment responses and clinical outcomes. Traditionally, breast cancer is classified into subtypes based on gene expression profiles; these subtypes, namely intrinsic subtypes, include luminal A, luminal B, basal-like and HER2-enriched breast cancer. This molecular taxonomy, however, could only be appraised through transcriptome analyses. We aim to classify breast cancer intrinsic subtypes using un-annotated approach using deep learning models.Methods: 388 pathological whole slide images (WSIs) from TCGA-BRCA dataset were downloaded from TCGA-GDC portal. These WSIs underwent patches generation and normalization using PyHIST tool and Macenko algorithm, respectively. Laplacian algorithm was applied to remove patches with blurry areas and pixelated. The remaining patches (n = 1,833,889) were divided into 3 parts for training (70%), testing (5%) and validation (25%). We applied a 2-step transfer learning with 2 pre-trained models, namely ResNet50, ResNet101, Xception and VGG16, which have been trained on another in-house breast cancer pathological image dataset. Results: these four models shown promising classification results of 4 breast cancer intrinsic subtypes with accuracy ranged from 0.68 (ResNet50 model) to 0.78 (ResNet101 model) in both testing and validation sets. The average AUC score for these models were from 0.88 (ResNet50 model) to 0.94 (ResNet101 model), whereas ResNet101_imgnet with “imagenet” weight archived an accuracy of 0.73 and AUC of 0.92. The overall accuracy of patient-wise prediction even shown a higher average accuracy of 0.914. These models’ prediction visualization was also used to demonstrate that the process of model learning was based on pathological cells’ clusters. Conclusion: Our study demonstrated the feasibility and capability of the deep learning model in classifying breast cancer intrinsic subtypes without region of interest annotation, which wound facilitate the clinical applicability of proposed models.

Citation Format: Chi-Cheng Huang, Nam Nhut Phan, Ling-Ming Tseng. Predicting molecular subtypes of breast cancer using [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-15.
Abstract P1-06-08: Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells
Authors: Malladi Srinivas
Published: March 2022

HER2+ breast cancer patients presenting with either synchronous (S-BM), latent residual (Lat) or metachronous (M-BM) brain metastases have poor survival outcomes. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Employing isogenic HER2+ breast cancer brain metastasis models, we show metabolic diversity and plasticity within brain-tropic cells determines metastatic fitness. Lactate secreted by aggressive metastatic cells (S-BM and M-BM) or lactate supplementation to mice bearing latent residual disease limits innate immune surveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as latent residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models.

Citation Format: Srinivas Malladi. Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-08.
Abstract P1-18-10: A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC)
Authors: Howell Sacha J , Kenny Laura M , Lord Simon , Krebs Matthew G , Arkenau Tobias , Baird Richard , MacPherson Iain R , Bahl Ash , Clack Glen , Ainscow Edward , Barrett Anthony GM , Dickinson Paul A , Fuchter Matthew J , Lehnert Manfred , Ali Simak , McIntosh Stuart , Coombes Charles
Published: March 2022

Background: CDK7 inhibition is a promising therapeutic strategy in cancer. CDK7 is a key kinase, regulating cell division, transcription and nuclear receptor function [1]. Although recent advances have been made in the treatment of TNBC this disease is still one of significant unmet need. Materials and Methods: Tolerability and efficacy of Samuraciclib were assessed in a TNBC expansion cohort of the first in human study of Samuraciclib. These patients had metastatic or locally advanced TNBC and had received prior taxane and anthracycline therapy including at least one line of chemotherapy for metastatic or locally advanced disease. Results: From 29th January 2019 to 12th April 2021, 23 women with advanced TNBC were recruited and dosed with Samuraciclib 360mg OD. Treatment has generally been well tolerated with all patients remaining on treatment until disease progression. The most common adverse drug reactions (AE) were: G1-2 Nausea (96%), Vomiting (52%) and Diarrhea (91%). There were 4 dose reductions to manage upper GI adverse events of nausea and/or vomiting. G3 events were as follows: 2 Grade 3 Diarrhea, 1 Grade 3 Vomiting, 1 Grade 3 Fatigue, 1 Grade 3 Stomatitis, 1 Grade 3 Anaemia and 1 Grade 4 Thrombocytopenia21 patients have had follow-up evaluations for assessment of efficacy. Stable disease was achieved in 14 patients, 1 with partial response (being on treatment for 72 weeks) and 7 patients with progressive disease; two additional patients remain on compassionate use treatment, following disease progression by RECIST. 5 patients have been on treatment for at least 24 weeks of whom 3 have exceeded 1 year. Conclusions: Samuraciclib demonstrated an acceptable safety and tolerability profile with evidence of antitumour activity in advanced TNBC. References1.Patel et al. ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. Mol Cancer Ther. 2018. doi: 10.1158/1535-7163.MCT-16-0847. PMID:29545334.

Citation Format: Sacha J Howell, Laura M Kenny, Simon Lord, Matthew G Krebs, Tobias Arkenau, Richard Baird, Iain R MacPherson, Ash Bahl, Glen Clack, Edward Ainscow, Anthony GM Barrett, Paul A Dickinson, Matthew J Fuchter, Manfred Lehnert, Simak Ali, Stuart McIntosh, Charles Coombes. A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-10.
Abstract P1-19-02: Repurposing the FOXO4 senolytic against triple-negative breast cancer
Authors: Putavet Diana , Baar Marjolein , Shi Tao , Lehmann Johannes , Leyten Tim , Bouma Esmee , Khalil Antoine , Vos Harm-Jan , Burgering Boudewijn , Dansen Tobias , Derksen Patrick , de Keizer Peter
Published: March 2022

Metastatic breast cancer is the second most common cause of cancer-related death in women. Triple Negative Breast Cancer (TNBC) has tan especially poor prognosis partly due to these tumors lacking relevant molecular targets. The most commonly mutated gene in TNBC is the tumor suppressor TP53. Mostly, p53 mutations give rise to stably expressed proteins with tumor promoting functions. Therefore, there is an urgent need for therapeutics that can target p53-mutated TNBCs. Here we show that an anti-senescence compound can target metastatic cancers. We found that, in TNBCs, mutant p53 attained a distinctive conformation that has novel oncogenic roles through binding to the transcription factor Forkhead box O (FOXO) 4 sequestered within promyelocytic leukemia (PML) foci. Since these nuclear structures are specific to senescent cells, we tested the senolytic FOXO4 peptide. In cytotoxicity experiments, we found this compound to target TNBCs specifically over other breast cancer subtypes. Most importantly, these compounds decrease metastatic burden in the most commonly-used mouse model for human breast cancer metastasis. In summary, our results demonstrate that mutant p53-driven cancers presented senescent cell-specific characteristics that makes them a great candidate for the FOXO4-directed anti-senescence therapy. We expect that creative repurposing of senolytics to translate to other types of cancer that are driven by mutant p53.

Citation Format: Diana Putavet, Marjolein Baar, Tao Shi, Johannes Lehmann, Tim Leyten, Esmee Bouma, Antoine Khalil, Harm-Jan Vos, Boudewijn Burgering, Tobias Dansen, Patrick Derksen, Peter de Keizer. Repurposing the FOXO4 senolytic against triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-02.
Abstract P2-12-06: Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy
Authors: Yang Yang , Chen Xue , Fan Zhaoqing , He Yingjian , Xie Yuntao , Li Jinfeng , Wang Tianfeng , Ouyang Tao
Published: March 2022

Objective: No consensus up to date suggesting whether patients with positive HR/negative HER-2 and positive lymph nodes breast cancer should receive additional adjuvant chemotherapy following a poor response to neoadjuvant chemotherapy to acquire a better DDFS. The main aim of this trial is to compare the 5-year DDFS between additional adjuvant chemotherapy plus endocrine therapy group and endocrine alone group following 4 cycles neoadjuvant chemotherapy. Method: A multicenter, open-label, randomized, controlled, phase 3 trial was conducted. All patients enrolled in the study were HR+ HER2- LN+ breast cancer patients completing four cycles neoadjuvant chemotherapy, with a non-responsive pathological result to neoadjuvant chemotherapy. The non-responsive criterion was defined as Miller and Payne staging grade1 to grade 3, or any grade of Miller and Payne staging but residual positive lymph nodes were found in surgical specimen. All enrolled patients were randomly assigned to receive four cycles non-cross resistant regimen plus endocrine therapy, or endocrine therapy alone. The primary endpoint was DDFS, and the secondary endpoint was iDFS and OS. Result: From October 2010 to September 2018, a total of 391 patients were enrolled for eligibility. The final ITT analysis compromised 379 patients (187 in adjuvant chemotherapy plus endocrine therapy group, and 192 in endocrine therapy alone group). After a median follow-up of 72.4 months, the 5-year distant disease free survival estimate was 92% (95% CI 88-96) in the adjuvant chemotherapy group and 90% (86-94) in the endocrine therapy alone group (HR 0.79, 95% CI 0.45-1.37) (P=0.401). In the prespecified CEF subgroup, the 5-year DDFS was 94% (95% CI 90-98) in adjuvant chemotherapy group, and 91% (95% CI 87-94) in endocrine group (HR 0.68, 95% CI 0.36-1.30) (P=0.249). In the exploratory analysis, we found a better 5-year DDFS trend in adjuvant chemotherapy group in ypN+ patients in CEF subgroup (P=0.196). Conclusion: A better 5-year DDFS trend in additional adjuvant chemotherapy plus endocrine therapy can be found for patients with positive HR/negative HER-2 and positive lymph nodes following a poor response to neoadjuvant chemotherapy.

Citation Format: Yang Yang, Xue Chen, Zhaoqing Fan, Yingjian He, Yuntao Xie, Jinfeng Li, Tianfeng Wang, Tao Ouyang. Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-06.
Abstract P3-03-21: Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean?
Authors: Keymeulen Kristien , Geurts Sandra , Kooreman Loes , Duijm Lucien , Engelen Sanne , Vanwetswinkel Sigrid , Luiten Ernest , Siesling Sabine , Voogd Adri , Tjan-Heijnen Vivianne
Published: March 2022

Background: For patients with ductal carcinoma in situ (DCIS), data about contralateral breast cancers detected by MRI at primary diagnosis and the impact of MRI use on the incidence and stage of contralateral breast cancers during follow-up are scarce. Methods: We selected all women diagnosed with a primary DCIS in the Netherlands in 2011-2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS and contralateral invasive breast cancer was assessed for patients who did receive an MRI upon primary diagnosis (MRI group) and for an age-matched control group without MRI. Incidence of contralateral disease during follow-up was calculated using competing risk methods.Results: Of the 8486 patients diagnosed with primary DCIS, 1571 (19%) received an MRI. In the MRI group, 0.8% of patients were diagnosed with a synchronous contralateral DCIS and 1.3% with synchronous contralateral invasive breast cancer. Median follow-up time was 6.4 years (IQR: 5.1-7.6). The estimated five-year cumulative incidence of synchronous plus metachronous contralateral DCIS was 2.0% (95% CI: 1.4%-2.8%)) for the MRI group and 0.9% (95% CI: 0.5%-1.5%) for the age-matched control group. The five-year cumulative incidence of contralateral invasive breast cancer was 3.5% (95% CI: 2.7%-4.5%) for the MRI group and 2.3% (95% CI: 1.6%-3.1%) for the age-matched control group. In patients aged <50 years, the cumulative incidence of metachronous contralateral DCIS was statistically significantly higher in the MRI group than in the age-matched controls (sHR= 4.22 (95%CI: 1.19-14.99), P=0.03). This was not the case in patients aged 50-74 years (sHR=0.89 (95%CI: 0.41-1.93), P=0.77). Conclusions: MRI led to more frequent detection of synchronous contralateral invasive breast cancers without lowering the number of metachronous contralateral invasive breast cancers. In patients aged below 50 years, MRI added to conventional imaging led to a persisting higher rate of DCIS diagnosed in the opposite breast, also without influencing the occurrence of invasive breast cancers being detected during the first five years of follow-up. Footnotes

Citation Format: Kristien Keymeulen, Sandra Geurts, Loes Kooreman, Lucien Duijm, Sanne Engelen, Sigrid Vanwetswinkel, Ernest Luiten, Sabine Siesling, Adri Voogd, Vivianne Tjan-Heijnen. Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-21.
Abstract P3-09-17: Systems-scale characterization of the human immunome in breast cancer for precision medicine
Authors: Yi Stephen
Published: March 2022

It becomes more clear that many deleterious cancer mutations could exhibit a 'gain-of-function' (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in breast cancer. Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output in breast cancer is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in cancer patients. To do so, we developed a network-based integrative model to prioritize potential immune responder genes. Identified mutations were enriched in essential protein domains and genes identified were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates in breast cancer. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted breast cancer therapeutics. This study is significant and innovative, as it demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics.

Citation Format: Stephen Yi. Systems-scale characterization of the human immunome in breast cancer for precision medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-17.
Abstract P3-18-14: Assessment of quality of life and objective cosmetic outcome of breast conserving surgery with or without latissimus dorsi mini-flap in breast cancer
Authors: Kim Jang-il , Han Yireh , Lim Changjin , Cheun Jong-Ho , Jung Ji Gwang , Kim Hong Kyu , Lee Han-Byoel , Moon Hyeong-Gon , Han Wonshik
Published: March 2022

Introduction : Latissimus dorsi mini-flap (LDMF) with breast conserving surgery (BCS) was introduced as a useful volume replacement technique when the tumor is located in upper or outer portion of breast and the tumor size is large requiring extensive excision of breast tissue. However few studies have assessed quality of life (QoL) and objective cosmetic outcome of LDMF in breast cancer surgery. We tried to evaluate those in patients who underwent BCS with or without LDMF. Methods : This study was a prospective, single-center cohort study of patients who underwent LDMF and BCS between 2011 and 2018. As a control, patients who underwent BCS without any volume replacement and the tumor size equal to or greater than 2.5cm on the upper or upper outer of the breast on preoperative imaging. Breast Q questionnaire and body photo were taken at least 1 year after surgery. Two breast surgeons and one plastic surgeon who did not performed LDMF assessed the cosmetic outcome of the patients with photo. Results : 62 patients were in the BCS with LDMF group and 58 patients were in BCS-only group. Pathologic tumor size was significantly larger in LDMF group than BCS-only group (LDMF 3.89cm vs BCS-only 2.92cm, p= 0.001 ). Psychosocial well-being (P= 0.024), physical well-being (P= 0.000), and satisfaction with surgeon (p= 0.006) were significantly better in the BCS-only group than in the LDMF group respectively. But, there were no significant difference in neither sexual well-being (p= 0.286) nor satisfaction for breast (p=0.278) between BCS and LDMF group. In the physicians assessment, there was no significant difference in the cosmetic outcome score between the two groups (LDMF 2.56/4 vs. BCS-only 2.58/4, p= 0.884). Conclusion : In conclusion, physician assessed cosmetic outcome of LDMF was equivalent to that of BCS without LDMF although the tumor size was significantly larger in patients with LDMF. Some inferiority of QoL might be due to postoperative pain or arm movement discomfort. We are planning to evaluate objective cosmetic results using BCCT.core software.

Citation Format: Jang-il Kim, Yireh Han, Changjin Lim, Jong-Ho Cheun, Ji Gwang Jung, Hong Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han. Assessment of quality of life and objective cosmetic outcome of breast conserving surgery with or without latissimus dorsi mini-flap in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-14.
Abstract P4-02-08: Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models
Authors: Shomali Maysoun , Guo Zhuyan , Cheng Jane , Sullivan Amy , El-Ahmad Youssef , Sun Fangxian , Sidhu Sukhvinder , Lee Joon Sang , Cai Hui , Pollard Jack , Debussche Laurent , Soria Chris , Bouaboula Monsif
Published: March 2022

Nearly 70% of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. Despite initial efficacy seen with endocrine therapies, approximately 40% of patients develop acquired resistance which ultimately limits the use of these agents even as most of these tumors continue to require ERα. The strategies to combat these cancers with resistance are not yet defined and represent the next major clinical challenge in ER+ breast cancer. Amcenestrant is an optimized oral SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity irrespective of ESR1 mutational status, and is currently being evaluated as monotherapy and in combination with CDK4/6 inhibitors and other targeted therapies for ER+ breast cancer patients in clinical trials. Here, we report that in preclinical models, amcenestrant achieved significant anti-tumor efficacy/regression as a monotherapy and strong synergistic activity when administered together with the CDK4/6 inhibitor, palbociclib, in subcutaneously xenografted endocrine resistant ER+ BC mouse models: ESR1-Y537S mutant-driven MCF7 tumor and HCI-013 PDX (patient-derived xenograft). Transcriptional profile analysis of xenograft tumor biopsies revealed the modulation of different pathways by SERD and palbociclib and highlighted crosstalk of ER and CDK4 signaling pathways. Interestingly, CDK4/6 inhibition by palbociclib induces partial activation of ER pathways as potential mechanism of tumor escape which is completely abolished by the combination treatment of amcenestrant with palbociclib. Early clinical data also showed that amcenestrant in combination with palbociclib, exhibited a favorable safety profile and encouraging antitumor activity in patients with endocrine resistant, ER+/HER2-, advanced breast cancer, which supports its potential to become a new endocrine backbone therapy for ER+ HER2- breast cancer. In conclusion, amcenestrant is an oral SERD, which exhibits significant anti-tumor activity as a single agent and shows synergistic activity with CDK4/6 inhibitor palbociclib in ER+ BC xenografts preclinically and in early clinical development.

Citation Format: Maysoun Shomali, Zhuyan Guo, Jane Cheng, Amy Sullivan, Youssef El-Ahmad, Fangxian Sun, Sukhvinder Sidhu, Joon Sang Lee, Hui Cai, Jack Pollard, Laurent Debussche, Chris Soria, Monsif Bouaboula. Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-08.
Abstract P4-05-13: Prognostic implication of Yin Yang 1 (YY1) overexpression in patients with primary breast cancer
Authors: Cha Chihwan , Park Hosub , Kim Chul Geun , Chung Min Sung
Published: March 2022

Background: YY1 is conserved transcriptional factor that highly expressed in various types of cancers. It regulates differential epigenetic pathways and protein modifications. However, there is still unknown whether YY1 overexpression has any prognostic significance in breast cancer patients. In this study, we evaluated YY1 expression levels using tissue microarrays and analyzed clinicopathologic characteristics with survival outcomes. Methods: Clinical information and tissue blocks were obtained retrospectively from 491 patients who underwent surgery at Hanyang University Hospital between 2002 and 2016. Immunohistochemical staining was performed using rabbit monoclonal antibody (ab-109237). YY1 expression was determined using H-score. Overexpression was defined as H-score ≥ 28.4 (mean value). Overall survival (OS) and disease-free survival (DFS) was analyzed by Kaplan Meier analysis. Results: Of 491 patients with primary breast cancer, 138 (28.1%) patients had YY1 overexpression. Luminal subtype (ER+/HER2-), early tumor stage, and low grade tumor were significantly associated with overexpression (P<0.0001). In patients with luminal subtype, overexpression was significantly correlated with early nodal stage and low proliferation index (Ki-67≤20%, P=0.014). After median follow up 67 months, YY1 overexpression was significantly associated with better prognosis (OS rates; 96.4% vs. 88.1%, P=0.038 and DFS rates; 92.0% vs. 79.2%, P=0.014). In luminal subtype, patients with overexpression showed better DFS (93.0% vs. 80.2%, P=0.043). In a Cox proportional hazards model, YY1 overexpression was independent significant prognostic factor after adjustment of ER/HER2 status and tumor size (hazard ratio; 0.5, 95% CI [0.26-0.98], P=0.042). Conclusion: YY1 overexpression is a better prognostic marker in patients with primary breast cancer, especially in luminal subtype.

Citation Format: Chihwan Cha, Hosub Park, Chul Geun Kim, Min Sung Chung. Prognostic implication of Yin Yang 1 (YY1) overexpression in patients with primary breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-13.
Abstract P4-07-30: Residual lymphovascular invasion: Predicts the outcome of neoadjuvant chemotherapy in locally advanced breast cancer
Authors: Elemam Omima , Elnaghi Khaled , Emarah Ziad , Alghanami Hossam , Abdelkhalek Seham
Published: March 2022

Background: Lymphovascular invasion (LVI) is known to be associated with a poor outcome in breast cancer patients. It indicates a highly proliferative cancer. Few studies examined the value of LVI as a predictor for outcome after neoadjuvant chemotherapy (NAC). The aim of this study to look for an association between survival outcomes and clinicopathological features in locally advanced breast cancer patients treated with NAC and to identify the predictors of nodal pathologic complete response (PCR). Methods:This study is a retrospective analysis of 224 women with locally advanced breast cancer who underwent NAC between 2011-2020. Kaplan-Meier analyses were used to assess the associations between disease-free survival (DFS) and overall survival (OS) and all clinicopathological variables including LVI in breast surgical specimens following NAC. Associations between nodal PCR and all clinicopathologic variables were assessed Results:Median follow-up was 29.9 months. Absence of nodal PCR (p.000), positive family history (p .027), clinical T4 (p.049), pathological TNM staging (p.016), high tumor grade (p .020),triple negative disease(p .016) and absence of tumor PCR (p.001) were associated with worse disease free survival. Absence of nodal PCR (p.002), high BMI (p.039), multicentric disease (p.026), high tumor grade, triple negative disease (p.018), and absence of tumor PCR (p.005) were associated with worse overall survival. LVI was found in 53 of surgical specimens (23.7%). It was associated with worse DFS (HR) (2.967) 95% CI (1.7-4.9), p.000 and overall survival (HR) (3.05) 95% CI (1.525-6.09), p.002). Nodal PCR significantly correlated with T stage (p .013), LVI (p.000), ER status (p.004), PR status (p.003), Her2neu status and IHC score (p.000), tumor subtype (p.000), tumor PCR (p.000), DFS (p.000), and OS (p.000). Conclusion:LVI is significantly associated with worse DFS and OS in locally advanced breast cancer patients treated with NAC. This data confirmed the previously published recommendation to add LVI to the pathological staging system. LVI may be further explored as a guide for adjuvant treatment options in clinical trials. Nodal PCR is another significant predictor of outcome and is associated significantly with tumor PCR and LVI. Both tumor PCR and LVI can be used as criteria for axillary surgery omission in future trials.

Citation Format: Omima Elemam, Khaled Elnaghi, Ziad Emarah, Hossam Alghanami, Seham Abdelkhalek. Residual lymphovascular invasion: Predicts the outcome of neoadjuvant chemotherapy in locally advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-30.
Abstract P5-05-10: Inhibition of FASN as a potential treatment of advanced therapy-resistant breast cancer
Authors: Balinda Henriette U
Published: March 2022

INTRODUCTION: The majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and is overexpressed in more aggressive and therapy-resistant tumors, including breast cancers. METHODS: The effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen-resistant and fulvestrant-resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. RESULTS: TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant and fulvestrant-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. CONCLUSION: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.

Citation Format: Henriette U Balinda. Inhibition of FASN as a potential treatment of advanced therapy-resistant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-10.
Abstract P5-11-03: Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment
Authors: Ritter Andreas , Roth Susanne , Friemel Alexandra , Kreis Nina-Naomi , Louwen Frank , Solbach Christine , Yuan Juping
Published: March 2022

It is well documented that obesity, characterized by an increased body mass index (BMI≥30), is an important risk factor for the development of aggressive breast cancer (BC), which is associated with a reduced overall survival rate and decreased treatment response. The tumor microenvironment (TME), a cellular network majorly constructed by adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells, impacts progression of breast cancer and treatment response of patients. This study aims to examine how obesity influences the functional characteristics of bASCs in comparison to lean bASCs in the TME. To address this issue, various molecular, biological and cellular methods are applied including transcriptomic profiling and functional assays to characterize at first the features of bASCs in the TME (adjacent to tumor; -aT/distant to tumor; -dT) in obese (ob-) and lean (ln-) bASCs (n=5, for each group) patients with breast cancer. Second, based on the transcriptomic data, we investigated the interaction of bASCs with triple negative as well as triple positive BC cell lines in 3D-spheroids and in standard 2D-cell culture conditions.Indicated by the gene signature the TME shifts bASCs towards a cancer supporting phenotype with a significant deregulated protein expression, cytokine/chemokine secretion, and reduced differentiation capacity. These changes affect critically the cell-cell interaction of BC cells with bASCs. bASCs isolated adjacent to the tumor increase the malignancy of BCs by stimulating the proliferation, migration, invasion and chemoresistance of these cells significantly. These observed effects are further enhanced by ob-aT bASCs. In conclusion, this study identifies over 900 genes deregulated in bASCs adjacent to breast cancer. Many of these genes are associated with pathways known for the development of malignant cells. Moreover, it clarifies differences in obese versus lean bASCs and their impacts on progression of breast cancer cells.

Citation Format: Andreas Ritter, Susanne Roth, Alexandra Friemel, Nina-Naomi Kreis, Frank Louwen, Christine Solbach, Juping Yuan. Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-11-03.
Abstract WS2-1: Genome editing in human organoids as new models for discovery
Authors: Rosenbluth JM
Published: March 2022

Use of human organoids as new models for discovery. Despite significant advances, there are circumstances where mouse models remain inadequate to model cancer. Human organoid cultures are becoming established as a useful adjunct to mouse models because they enable the propagation of both normal and cancerous tissues in the lab for functional studies, disease modeling, and drug screening. Organoids can be generated from induced pluripotent stem cells or directly from donor tissue samples (e.g. normal breast tissue or tumors). In the latter approach, breast organoid cultures are grown in a hydrogel that mimics the basement membrane and are bathed in a cocktail of growth factors, vitamins, and compounds that mimic the microenvironment provided by stroma, resulting in the growth of cells in a polarized fashion to recapitulate breast acinar- and duct-like structures. Breast epithelial cells within organoids are able to differentiate into all of the major mammary epithelial lineages, and hence organoids can be used to study several types of epithelial lineages and their relative contributions to tumor development. In addition, breast cancer organoids can be used to expand heterogeneous populations of tumor cells for in vitro assays. For example, genome editing approaches can be used to model mutations associated with breast cancer, and compound screening approaches can facilitate target discovery. In this educational talk, we will review some of these recent advances, consider advantages and disadvantages of this model system, and discuss some practical considerations for bio-banking efforts and downstream applications.

Citation Format: JM Rosenbluth. Genome editing in human organoids as new models for discovery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr WS2-1.
Are You a TMBeliever? Mutations and Atezolizumab Response in Solid Tumors
Authors: Maron Steven B. , Klempner Samuel J.
Published: March 2022

Optimizing the utility of tumor mutational burden in solid tumors remains an unmet need and a clinical knowledge gap. Using a centrally determined cutoff of ≥16 mut/Mb, Friedman and colleagues demonstrate an ability to enrich for atezolizumab response in a pretreated pan-cancer multibasket study.

See related article by Friedman et al., p. 654 (4).
Radiomics versus Conventional Assessment to Identify Symptomatic Participants at Carotid Computed Tomography Angiography
Authors: Dong Zheng , Zhou ChangSheng , Li HongXia , Shi JiaQian , Liu Jia , Liu QuanHui , Su XiaoQin , Zhang FanDong , Cheng XiaoQing , Lu GuangMing
Published: March 2022

Introduction: Carotid computed tomography angiography (CTA) is routinely used for evaluating the atherosclerotic process. Radiomics allows the extraction of imaging markers of lesion heterogeneity and spatial complexity. These quantitative features can be used as the input for machine learning (ML). Therefore, in this study, we aimed to evaluate the diagnostic performance of radiomics-based ML assessment of carotid CTA data to identify symptomatic patients with carotid artery atherosclerosis. Methods: In this retrospective study, participants with carotid artery atherosclerosis who underwent carotid CTA and brain magnetic resonance imaging from May 2010 to December 2017 were studied. The participants were grouped into symptomatic and asymptomatic groups according to their recent symptoms (determination of ipsilateral ischemic stroke). Eight conventional plaque features and 2,107 radiomics parameters were extracted from carotid CTA images. A radiomics-based ML model was fitted on the training set, and the radiomics-based ML model and conventional assessment were compared using the area under the curve (AUC) to identify symptomatic participants. Results: After excluding participants with other stroke sources, 120 patients with 148 carotid arteries were analyzed. Of these 148 carotid arteries, 34 (22.97%) were classified into the symptomatic group. Plaque ulceration (odds ratio [OR] = 0.257; 95% confidence interval [CI], 0.094–0.698) and plaque enhancement (OR = 0.305; 95% CI, 0.094–0.988) were associated with the symptomatic status. Twenty radiomics parameters were chosen to be inputs in the radiomics-based ML model. In the identification of symptomatic participants, the discriminatory value of the radiomics-based ML model was significantly higher than that of the conventional assessment (AUC = 0.858 vs. AUC = 0.706, p = 0.021). Conclusion: Radiomics-based ML analysis improves the discriminatory power of carotid CTA in the identification of recent ischemic symptoms in patients with carotid artery atherosclerosis.
Simultaneous Use of Two Recombinant Blood Group Antigens for Identification of Rare Complex Antibody Mixtures
Authors: Syrjälä Teemu
Published: March 2022

Background: Antibodies to high-frequency antigens in red blood cells make antibody identification difficult for immunohaematology laboratories to conduct using conventional methods, especially when the sample contains multiple co-existing allo-antibodies. This study presents the successful application of an antibody inhibition method based on recombinant blood group antigens (rBGAs) to identify mixtures of allo-antibodies as well as an antibody to a high-frequency antigen observed in two patients. Methods: rBGAs were utilised in detecting antibodies in two samples where more than one antibody was inhibited simultaneously from polyreactive plasma. The inhibition step was followed using conventional column agglutination techniques. Results: In the sample of Patient A, anti-f and the previously missed anti-Jkb were identified after simultaneous inhibition of anti-Yta and anti-Fya. The results of the sample of Patient B show anti-C and anti-M identified after simultaneous inhibition of anti-Ch1 and anti-Fya. Conclusions: The presented technique is an excellent supporting aid in antibody identification used with conventional column agglutination techniques. Antibody inhibition using mixed rBGAs allows reference and routine laboratories to identify rare antibody mixtures in a fast and efficient manner. Routine laboratories may be able to conduct difficult antibody identifications independently without referring these samples to a reference laboratory, resulting in faster identification results and elimination of delay in patient care. Simultaneous rBGA inhibition is an off-label technique not instructed in the user manual of rBGA and should be used with caution.
Office-Based Procedures in the Management of Hemorrhoidal Disease: Rubber Band Ligation versus Sclerotherapy – Systematic Review and Meta-Analysis
Authors: Salgueiro Paulo , Ramos Maria Inês , Castro-Poças Fernando , Libânio Diogo
Published: March 2022

Introduction: The most frequently used office-based procedures in hemorrhoidal disease (HD) are rubber band ligation (RBL) and sclerotherapy. Few studies have been published comparing the various types of instrumental therapy. The aim of this systematic review and meta-analysis was to compare the efficacy and safety of sclerotherapy and RBL. Methods: Three online databases were searched. Efficacy (control of symptoms, prolapse, bleeding and pain, patients’ satisfaction, and disease recurrence) and safety (complications, such as pain and bleeding) were the assessed outcomes. Pooled relative risks (RR) were computed for each outcome using a random-effects model, and heterogeneity was assessed by Cochran’s Q test and I2. Results: Six RCTs and three cohort studies were included. Control of prolapse and bleeding was significantly higher with RBL (93.1% RBL vs. 66.4% sclerotherapy, RR 1.34, 95% CI 1.12–1.60 and 89.1% RBL vs. 78.7% SCL, RR 1.17, 95% CI 1.02–1.34, respectively). Both techniques had similar results in terms of pain relief, overall control of symptoms, and risk of recurrence at 3 months. Although patient satisfaction was significantly higher with RBL (77.8% RBL vs. 46.7% sclerotherapy, RR 1.59, 95% CI 1.01–2.50), post-procedural pain was significantly higher with this technique (24% RBL vs. 14% sclerotherapy, RR 1.74, 95% CI 1.32–2.28). There was no significant difference regarding post-procedure bleeding (11.1% RBL vs. 8.7% sclerotherapy, RR 1.29, 95% CI 0.86–1.94). In the subgroup analysis, according to the HD grade, post-procedure pain was higher with RBL only in HD grade II (vs. HD grade I–III). Conclusions: RBL performs better than sclerotherapy in controlling HD symptoms, specifically prolapse and bleeding, although post-procedural pain is a frequent complication. Recurrence is similar with both procedures. While waiting for the publication of results with sclerotherapy with new sclerosants, RBL remains the office-based treatment of choice in HD.
Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia
Authors: Cao Yuan , Zhang Ding-Ding , Mu Jing-Yu , Liu Yi-Ming , Gao Feng , Han Fei , Zhai Fei-Fei , Zhou Li-Xin , Ni Jun , Yao Ming , Li Ming-Li , Jin Zheng-Yu , Zhang Shu-Yang , Cui Li-Ying , Shen Yong , Zhu Yi-Cheng
Published: March 2022

Background: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. Methods: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. Results: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (β = 0.67, 95% CI: 0.54–0.85, p = 0.001; β = 0.79, 95% CI: 0.68–0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (β = 0.07, 95% CI: 0.03–0.11, p < 0.001). Conclusion: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.