bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot evaluation of allostatic load and breast cancer characteristics in a predominantly Han Chinese population.
Authors: Gou Wenjing , Zou Qin , Carlos Ruth C. 
Published: June 2024

e12570 Background: To determine the effects of allostatic load (AL), a measure of cumulative physiological effects of chronic stress due to adverse social determinants of health, on breast cancer (BC) characteristics in Chinese individuals. Methods: A pilot sample of185 women with newly diagnosed BC at Sichuan People’s hospital from 2018 to 2023 and complete AL data were included. AL used 10 markers (total cholesterol, low-density lipoprotein, albumin, glomerular filtration rate, white blood cell count, C-reactive protein, systolic and diastolic blood pressure, body mass index and heart rate). AL was assigned 1 point for each marker value in the worst quartile. The sum of the points represented the AL composite measure. Using linear and logistic regression, we determined the association of AL with age and educational attainment and with tumor ER+ and PR+ status. Results: Participants were 98.37% Han Chinese, mean age 51 (range 27-78). 23.24% attained college-level education or above. Higher AL trended to correlate with less than college-level educational attainment (coefficient=-0.60, p=0.058). In a univariable model, AL correlated with ER+ (OR=0.80, P=0.039) and PR+ (OR=0.81, P<0.001) BC. Adjusting for age and educational attainment, AL trends remained positive but not significant with ER+ BC (OR =0.82, P=0.092). Conclusions: Similar to US patients, AL may represent a physiologic correlate of adverse social conditions and worse BC characteristics. Results remain to be confirmed in a larger population.
Ipsilateral recurrence and breast cancer outcomes in carriers of BRCA1/2 pathogenic variants according to locoregional treatments.
Authors: Bernstein-Molho Rinat , Haisraely Ory , Galper Shira , Gal-Yam Einav Nili , Kaidar-Person Orit 
Published: June 2024

e12584 Background: Our previous study of 255 breast cancer (BC) patients, carriers of BRCA1/2 pathogenic variants (PV), showed that patients who underwent mastectomy without post-mastectomy radiotherapy (PMRT) had higher rates of local recurrence (LR) than those who underwent PMRT or breast-conserving therapy (BCT). Our aim was to verify our previous findings in a larger cohort. Methods: Clinical data was extracted from the medical records of BRCA1/2 mutation carriers with BC, treated at a single institution between 1/2006-12/2022. Data extracted included demographics, tumor characteristics, disease stage, surgical and oncological treatment, use of RT and disease outcomes. Results: Overall, 481 BC patients with BRCA1/2 germline mutations were identified, 20 of them presented with synchronous bilateral disease. Median follow-up time was 75.3 months (range 12.5-211). After excluding 16 patients with metastatic de novo disease and 1 patient not operated for medical reasons, 464 patients with 484 primary tumors were analyzed. Of these, 234 (48.3%) mastectomies (84% were skin- or nipple-sparing, SSM/NSM, 16% total mastectomy) and 250 (51.7%) BCT were performed. In the non-PMRT group (n=153) there was earlier disease stage at diagnosis (77.6% of tumors were Tis and T1N0) compared to the PMRT group (n=81) and BCT group (4.9% and 45%, respectively, p<0.001). All had free surgical margins. LR rate in the study cohorts was 20/153 breasts (13.1%) in the non-PMRT group compared with 1/81 breasts (1.2%) in the PMRT group (p=0.003), and 16/250 (6.4%) in the BCS group (p=0.024). All but one recurrence were invasive. Cumulative incidence of LR at 5 and 10 years was 14.1% and 15.9% in the non-PMRT, compared to 4.4% and 9.4% in BCT group, respectively (p=0.034). No significant difference in overall survival was observed (p=0.39). Conclusions: BRCA1/2 PV carriers treated with mastectomy without PMRT had higher rates of LR than those who underwent mastectomy and PMRT or BCT, despite earlier stage disease. Further studies are needed to compare these outcomes to non- BRCA1/2 carriers and find means to improve local control in these patients.
Analysis of risk factors for recurrence within 12 months after surgery in patients with breast cancer receiving neoadjuvant therapy at a Brazilian cancer center.
Authors: Rossato de Almeida Guilherme , Cesca Marcelle Goldner , de Albuquerque e Rodrigues de Sousa Débora Guilherme , Cavalcanti Balint Flavia , Leite Luciana de Moura , Lima Vladmir Cordeiro , Moraes Sanches Solange , Celeste Tavares Monique 
Published: June 2024

e13039 Background: Early recurrence following treatment for localized breast cancer typically occurs within 5 years, and is commonly linked to high-risk clinicopathologic factors. However, literature focusing on risk factors for earlier recurrence timeframes is scarce, particularly within the neoadjuvant treatment population. Therefore, this study aims to investigate potential predictors for recurrence within 12 months post-surgery in breast cancer patients submitted to neoadjuvant therapy. Methods: This is an observational, descriptive, retrospective study involving 310 patients with recurrent breast cancer who received neoadjuvant therapy between January 2007 and March 2022, at AC Camargo Cancer Center in São Paulo, Brazil. Patients were compared based on relapse time after surgery (<12 months or ≥12 months), and risk factors were analyzed using the Chi-Square test or Fisher’s Exact test. Results: From 310 patients analyzed, 108 relapsed within 12 months and 202 after this period. Factors predicting recurrence in less than 12 months included: Histologic grade (HG) III ( p < 0.01); nuclear grade (NG) III ( p < 0.001); mitotic counts >20/mm2 ( p = 0.02); Ki67 > 20% ( p = 0.010); triple negative breast cancer (TNBC) and HER2+/HR- subtypes ( p < 0.001); interruption of neoadjuvant therapy due to disease progression or toxicity ( p < 0.001); chemotherapy dose reduction or delay ( p = 0.001); omission of adjuvant radiotherapy ( p < 0.001) and interruption of adjuvant HER2 targeted therapy ( p < 0.001). Menopausal status, Residual Cancer Burden (RCB) index, type of surgery and clinical stage showed no significant correlation with the outcome. Conclusions: Recurrence in less than 12 months was associated with intrinsic factors, such as HG III, NG III, high mitotic counts, Ki67 > 20%, TNBC, as well as interruption or delay of neoadjuvant therapy, omission of adjuvant radiotherapy and interruption or delay of HER2 targeted therapy, pointing out potential risk factors in this population.
Profile of breast cancer in patients with Li-Fraumeni syndrome: An institutional experience.
Authors: S G Nithin , Gogia Ajay , Pramanik Raja , Deo S.V.S , Sharma Daya Nand , Batra Atul , Mathur Sandeep , Prasad Chandra Prakash 
Published: June 2024

e13042 Background: Li Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome, associated with multisystem cancer predisposition. Considering the rarity of this syndrome, studies are very sparse on survival outcomes of breast cancer with germline TP53 mutation and there exists discrepancy amongst the results. Methods: This retrospective observational study included 17 patients with germline TP53 mutated breast cancer registered at All India Institute of Medical Sciences (AIIMS), New Delhi, India between the period of 1st April 2016 to 31st Dec 2023. Among the 577 high-risk breast cancer patients, who underwent germline mutation testing, 231 (40.03%) cases had pathogenic mutation [145(25.12%) were BRCA mutated,15 (2.59%) were TP53 mutated, and the rest were others pathogenic variant]. All the TP53 mutations were crosschecked via the ClinVar mutation database to be classified as pathogenic. Results: The median age of 15 patients was 31 years (23-55) and 12 (80%) cases were premenopausal. All the patients had breast cancer as the index malignancy. The Stage distribution (AJCC-7th edition) Stage I, 1(6.6%); Stage II, 7 (46.6 %); Stage III, 4 (26.6 %); and Stage IV, 3 (20 %). Eight cases (53.3%) were HER2 positive, 4 (26.6%) were hormone receptor-positive, and 3 (20%) were Triple-negative breast carcinoma (TNBC). Ten (10) patients received neoadjuvant chemotherapy and 6 (60%) had a complete pathological response. Eight cases (53.3%) cases had a significant family history with 9 (60%) of them having at least one first-degree relative with cancer and two had more than one first-degree relative with cancer. One patient had a family history of LFS. The most common familial cancer was breast, followed by lung, GI malignancies, brain tumor, and sarcoma. Synchronous breast cancer was seen in 2 patients, synchronous malignancies were seen in 4 cases (one patient: each with lung adenocarcinoma, periampullary carcinoma, carcinoma colon, and synovial sarcoma, along with breast cancer), Four patients (26.6%) had metachronous cancers: lung cancer, ovarian carcinoma, contralateral breast cancer, and high-grade sarcoma respectively. The most common mutations were point mutations ( n = 11, 73.3%) followed by frameshift mutations ( n = 4, 26.6%). The subtypes of point mutations included missense mutations ( n = 9) and nonsense mutations ( n = 2) with the most common aberration being a replacement of arginine with glycine (c.743G>A, p. Arg248Gln) and locus being exon 7. The median disease-free survival was 41 months and progression-free survival was 15 months. Conclusions: The prevalence of TP53 mutation in our breast cancer patients is 2.5%. With standard treatment protocols, the overall survival of LFS-associated breast cancer is similar to the historic cohort of patients without any germline mutation. Active surveillance of the patient and family screening is imperative, for all positive cases.
Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).
Authors: Mahadevia Himil , Chandra Simran , Gosch Kensey , Khamees Ibrahim , Sharma Parth , Gast Kelly C. , Pluard Timothy J. , Hensing Whitney L. 
Published: June 2024

e13084 Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB >10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.
Efficacy and safety of sacituzumab govitecan in HR+/HER2– advanced breast cancer: A comprehensive systematic review and meta-analysis.
Authors: Qureshi Zaheer , Jamil Abdur , Altaf Faryal , Siddique Rimsha 
Published: June 2024

e13085 Background: Breast cancer is the most commonly diagnosed cancer in women, with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) being the predominant subtype. Sacituzumab govitecan, a novel antibody-drug conjugate, has emerged as a promising treatment for metastatic HR+/HER2– breast cancer. The aim of this systematic review and meta-analysis was to evaluate its efficacy and safety. Methods: Adhering to PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, and Cochrane databases up to December 2023. We included clinical trials and observational studies evaluating sacituzumab govitecan in patients with HR +/HER2–advanced breast cancer. The primary outcome was progression-free survival (PFS), while the secondary outcomes included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and adverse event profiles. Various statistical models were used for the analysis. Results: Nine studies met the inclusion criteria, and three were suitable for meta-analysis. The pooled analysis showed a Hazard Ratio (HR) of 0.57 for PFS, indicating a significant reduction in disease progression, and an HR of 0.68 for OS, suggesting improved survival. The treatment also significantly increased the likelihood of tumor response and clinical benefit but was associated with a higher occurrence of adverse events. Conclusions: Sacituzumab govitecan demonstrated significant efficacy in treating HR+/HER2– advanced breast cancer, reducing disease progression and mortality. However, its use is associated with a high rate of adverse events. These findings highlight the potential of Sacituzumab govitecan as a valuable addition to breast cancer treatment regimens, warranting further investigation and long-term studies.
A novel B7-H3 x CD3 bispecific T-cell engager for the treatment of B7-H3+ tumors.
Authors: Li Feng , Liu Ming , Hua Yanan , Wei Xuemei , Qin Luying , Cao Guangcan , Yang Daniel Chunxu , Zhang Wenjun 
Published: June 2024

e14509 Background: B7-H3 (CD276) is a transmembrane protein highly expressed in solid tumors but with limited expression in normal tissues. Its presence is strongly associated with the inhibition of T-cell activity, cancer progression, and invasion. Furthermore, B7-H3 is strongly associated with poor prognosis and reduced patient survival. Given its crucial role in tumor biology, B7-H3 has emerged as an attractive therapeutic target for drug development. We utilized ExMab heterodimer platform and common light chain technology to develop EX105, a next-generation B7-H3×CD3 bispecific antibody. This innovative T-cell engager exhibits excellent anti-tumor activity in mouse models and good safety profile in NHP tox study. Methods: EX105 was generated using ExMab heterodimer platform and common light chain technology to form a heterodimeric IgG1 structure. Preclinical pharmacology studies, efficacy, and safety were evaluated. Anti-tumor activity study of EX105 includes in vitro T-cell cytotoxicity assays and in vivo PBMC reconstituted xenograft mice models. Preclinical safety evaluation of EX105 was performed through GLP single-dose and repeat-dose tox studies in non-human primates (NHPs). Results: Based on ELISA and FACS analyses, EX105 can bind to both human and cynomolgus monkey B7-H3 and CD3 antigens. Furthermore, SPR data suggest that EX105 exhibits a high affinity to B7-H3 and a much lower affinity to CD3. In consistent with that, EX105 only induced relatively low cytokine release. Nevertheless, EX105 showed a potent in vitro T cell cytotoxicity against B7-H3+ tumor cell lines. The in vivo anti-tumor activity of EX105 was further determined in several tumor xenograft models. Treatment with EX105 resulted in remarkable tumor regression in both “hot” tumor model and “cold” tumor model, indicating its effectiveness across a range of tumor types. Tox study in NHPs showed minimal adverse effects and no liver impairment after EX105 administration, even at high doses. The cytokine release data observed in this study suggests a good safety profile of EX105, with much lower cytokine release compared to other T cell engagers. Conclusions: These findings collectively indicate that EX105 has the potential to become a promising therapeutic agent for the treatment of various B7-H3 positive cancers. The first-in-human clinical trial for patients with advanced B7-H3 positive cancers is due to start.
The effect of resting dendritic cells on overall survival in the hepatocellular carcinoma tumor microenvironment.
Authors: Hanona Paul , Jairath Neil , Farha Mark , Yohanathan Lavanya , Ezekwudo Daniel , Jaiyesimi Ishmael A. 
Published: June 2024

e14559 Background: Hepatocellular carcinoma (HCC) continues to have a poor prognosis even in the advent of new immunotherapy regimens. An area of growing interest in HCC is its tumor immune microenvironment. Classifying the immune microenvironment based on available genomics can lead to insights on prognosis and treatment, especially regarding the role of immunotherapy. Methods: RNA sequencing data was extracted from The Cancer Genome Atlas (TCGA), specifically from the hepatocellular carcinoma section (n = 366). CIBERSORT was utilized to organize the immune cell fractions present for each patient sample. Radiant by Shiny was used to perform a linear regression elucidating the relationship between overall survival and several other variables including: age, gender, tumor stage, race, ethnicity, B-cells naïve, B-cells memory, plasma cells, CD8 T-cells, CD4 T-cells, T-cells follicular, T-cells regulatory, natural killer activated and resting cells, monocytes, macrophages (M0, M1, M2), dendritic cells activated and resting, mast cells activated and resting, eosinophils, and neutrophils. Subgroup analyses were also performed via radiant regarding gender, race, and resting dendritic counts. Results: Resting dendritic cells were independently prognostic of overall survival on multivariable analysis (p = 0.041). The coefficient of correlation was +164.53 showing a positive association between the number of resting dendritic cells and the overall survival. Subgroup analysis showed no difference in resting dendritic counts between males and females (p = 0.526). Also, there was no difference seen in resting dendritic counts between populations of Asians and African Americans (p = 0.873), Asians and Whites (p = 0.223), and between Whites and African Americans (p = 0.811). Conclusions: Patients with a higher number of resting dendritic cells in their tumor immune microenvironment had a better overall survival. There was no difference between males and females in the resting dendritic counts. Likewise, there was no difference in the resting dendritic counts between Asian, African American, and white populations. Resting dendritic cells have been shown to be enriched in hepatocellular carcinomas with a low tumor mutational burden. This is a paradigm that should be explored further in the context of immunotherapy. Resting dendritic cells are also in a state of plasticity as they go from resting to active. Future genomic analysis of the tumor microenvironment regarding this plasticity could also lead to enhancing treatment options.
YF550-C1, an E3 ligase inhibitor of CBL-B, to demonstrate T cell and NK cell activation and anti-tumor activities in syngeneic and PDX tumor model.
Authors: Ye Jie , Liu Tengfei , Liu Yahui , Liu Xueqiang , Wu Fan , Lu Tingting , An Na , Chai Yushuang , Lin Xingyu , Liao Xuebin 
Published: June 2024

e14570 Background: Casitas B-lineage lymphoma b (CBL-B) is one of ligase in E3 ubiquitin family, which mainly expressed in matured hematopoietic cells, including T and NK cells. Study showed that CBL-B deficiency upregulated interleukin-2 and interferon-gamma secretion during anti-CD3 and anti-CD28 stimulated TCR activation, even without co-stimulator anti-CD28[3]. Except T cells, CBL-B plays important role in NK cells as well. CBL-B was upregulated during NK cell activation. While downregulation of CBL-B enhanced the cytotoxicity of primary human NK cells against hematological cancer cell lines. In vivo studies proved that CBL-B deficiency protected mice from tumor growth by inducing antitumor immunity. Thus, CBL-B shows a promising target for cancer therapy. Methods: We developed a small molecule YF550-C1 that targeted CBL-B, and evaluated the activation on T cell and NK cell function, and the therapeutical effect on syngeneic tumor models. The T cell activation was indicated by levels of IL-2 and IFN-γ from CBL-B knockout or WT CD8+ T cells since stimulated with anti-CD3 or anti-CD3/28 for 48 hours. The resistance of PGE2-induced immunosuppressive was evaluated by measuring IL-2 and IFN-γ since human T cells treated with PGE2 and followed by series diluted YF550-C1 or comparable inhibitor cpd23. OVA specific antigen stimulated CD8+ T activation assay was conducted by coculture OT-1 CD8+ T cells and WT DC cells with 50:1 for 72 hours in the present of 5ug/ml OVA peptide and series diluted YF550-C1. The NK cell cytotoxicity was evaluated by co-culture human NK cells and K562-luc cells with 1.25:1 ratio in the present of 1000nM or 333nM YF550-C1, which indicated by luminance. Syngeneic mouse model that inoculated with different types of murine cancer cell lines was used to evaluate tumor growth. Results: CBL-B deficiency suppressed tumor growth in mouse tumor models and enhanced cytokines release in T cells upon TCR engagement. CBL-B inhibitor, YF550-C1, alleviated PGE2-mediated immunosuppression of human T cell activation. CBL-B inhibitor, YF550-C1, enhanced OVA-specific antigen stimulated CD8+ T cell activation. CBL-B inhibitor, YF550-C1, enhanced cytotoxicity of human NK cell against K562-luc cells. CBL-B inhibitor, YF550-C1, or in combinate with anti-PD-L1 suppressed tumor growth in syngeneic tumor models. Single-agent of CBL-B inhibitor YF550-C1 treatment was sufficient to suppress PD1/PD-L1 resistant NSCLC patient-derived tumor growth. Conclusions: These studies provided insight into the activity of the inhibitor of CBL-B, demonstrating that YF550-C1 displays excellently T cell activation, T cell immunosuppression alleviation, NK cell activation and antitumor activity in multiple preclinical tumor models. Our data showed that YF550-C1 is a promising candidate for cancer treatment as monotherapy or in combination with PD-L1 blockade.