bluuebunny/crossref_metadata_2025_split huggingface dataset:
OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results.
Authors: Schilder Russell J. , Shahin Mark S. , Edelson Mitchell , Rosenblum Norman G. , Douglas Ashley , Bhattacharya Saveri , Sahmoud Tarek , Burton Elizabeth , Bhatia Avnish K 
Published: June 2023

5601 Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .
Association of the Duffy-null allele and endometrial cancer characteristics: An effort to explore racial disparity in Black women with endometrial cancer.
Authors: Webster Emily M. , Martini Rachel , Kulkarni Amita , Narayan Priyanka , Chao Max , Cantillo Evelyn , Frey Melissa Kristen , Holcomb Kevin , Elemento Olivier , Davis Melissa , Chapman-Davis Eloise 
Published: June 2023

5603 Background: Efforts are needed to identify factors that account for the disparately high mortality in Black women with endometrial cancer. The Duffy antigen receptor for chemokines (DARC) is expressed on erythrocytes and endothelial cells and modulates levels of inflammatory chemokines in circulation and in tissues. The African ancestry-specific Duffy-null allele, in which erythrocyte expression and function of DARC is lost, is associated with worse breast cancer phenotypes and survival. Here, we characterize Duffy-null status and associated prognostic and clinical outcomes in patients with endometrial cancer. Methods: Patients with endometrial cancer were prospectively consented, and germline DNA was extracted from saliva or blood samples. Duffy-null genotype was determined using an allelic discrimination assay. Associations between Duffy-null genotype status and clinicopathologic characteristics were performed using Fisher’s Exact analysis. Results: 33 patients were enrolled (Table); 17 (51.5%) were Duffy-null, 5 (15.2%) were Duffy-null allele carriers, and 11 (33.3%) were non-carriers. Compared with non-carriers, Duffy-null patients were more likely to be Black (100% v 9.1%, p<0.0001) and have non-endometrioid histology (64.7% v 10%, p=0.0173). There was a trend towards higher rates of grade 3 histology (70.6% v 36.6%), intact tumor mismatch repair (MMR) (86.7% v 54.6%), estrogen receptor (ER) negative tumor status (25% v 10%), advanced stage (37.5% v 18.2%), and positive lymph nodes (25% v 0%) (Table). Over a minimum of 12 months of follow up, only Duffy-null individuals died from disease (4 v 0, p=0.0006). Conclusions: Duffy-null status was associated Black race, aggressive histologic subtypes, intact MMR mechanisms, and worse survival. Further investigation is needed to explore the underlying mechanism of the Duffy-null phenotype on endometrial cancer outcomes to better elucidate risk factors and underlying causes that may contribute to endometrial cancer disparities.[Table: see text]
Association of human epidermal growth factor receptor 2 expression with 21-gene recurrence score and survival among patients with estrogen receptor–positive breast cancer.
Authors: Ma Sung Jun , Gill Jasmin , Yendamuri Keerti , Yao Song , Oladeru Oluwadamilola Temilade , Singh Anurag K. 
Published: June 2023

563 Background: Trastuzumab-deruxtecan was recently shown to improve survival for metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer. HER2-negative breast cancer has been redefined as a group of heterogeneous entities. However, HER2-low status is not considered as a prognostic factor among patients with nonmetastatic breast cancer, and the role of HER2 expression levels in the setting of 21-gene recurrence score (RS) remains unclear. We performed an observational cohort study using a national oncology database to evaluate the association of HER2 expression levels with RS and survival among patients with estrogen receptor (ER)-positive breast cancer. Methods: The National Cancer Database was queried for women diagnosed between 2006 and 2018 with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with or without chemotherapy. HER2 expression levels were stratified by 3 groups: HER2-0 (immunohistochemistry [IHC] 0), HER2-1 (IHC +1), and HER2-2 (IHC +2 and in situ hybridization [ISH] negative). Logistic and Cox multivariable analysis (MVA) were used to identify factors associated with high RS (26 or higher) and overall survival (OS), respectively. Interaction term was analyzed to evaluate any heterogeneous associations in survival outcomes between HER2 levels and RS. Subgroup analysis was performed by repeating Cox MVA stratified by RS. Holm-Bonferroni correction was used to adjust for multiple comparisons, with p value less than 0.05 considered as statistically significant. Results: Among 108,973 women, 31,738 (29.1%), 52,839 (48.5%), and 24,396 (22.4%) patients had HER2-0, HER2-1, and HER2-2, respectively. Logistic MVA showed that, compared to HER2-0, HER2-2 was associated with higher RS (adjusted odds ratio [aOR] 1.09, 95% confidence interval 1.04-1.15, p < 0.001), but HER2-1 was not (aOR 0.96, 95% CI 0.91-1.00, p = 0.05). Cox MVA showed that both HER2-1 (adjusted hazards ratio [aHR] 1.03, 95% CI 0.97-1.10, p = 0.34) and HER2-2 (aHR 1.06, 95% CI 0.98-1.14, p = 0.14) were not associated with OS. There was an interaction between HER2 expression levels and RS (interaction p = 0.03). Among those with RS < 26, compared to HER2-0, HER2-2 was associated with worse OS (aHR 1.10, 95% CI 1.01-1.20, p = 0.02), but HER2-1 was not (aHR 1.04, 95% CI 0.97-1.12, p = 0.24). Among those with RS 26 or higher, both HER2-1 (aHR 1.00, 95% CI 0.88-1.13, p = 0.98) and HER2-2 (aHR 0.94, 95% CI 0.82-1.09, p = 0.41) were not associated with OS. Conclusions: To our knowledge, this is the largest study using nationwide oncology database to suggest that, when compared to HER2-0, HER2-2 was associated with higher RS and poor survival among patients with RS < 26. Further studies would be warranted to evaluate the role of HER2 expression levels for risk stratification to tailor interventions.
Correlation of gene signatures of Kaiso and LC3A/B protein expression with distinct tumor ecosystems and to predict response to breast cancer therapy.
Authors: Singhal Sandeep K. , Gardner Kevin 
Published: June 2023

566 Background: The multifunctional transcriptional repressor, Kaiso, is a member of the BTB/POZ (Broad complex, Tramtrak, Bric `aBrac/Pox zinc finger) family of zinc finger proteins. Kaiso protein levels in both the nucleus and the cytoplasm have each been shown to be highly sensitive and independent predictors of overall breast cancer survival. Through the use of gene signatures and/or gene modules developed through the analysis of RNA-seq data from breast cancer patients following biomarker stratification by either nuclear Kaiso, cytoplasmic Kaiso, or the Kaiso’s functional downstream target LC3A/B, we demonstrate the utility of Kaiso and LC3A/B derived signatures as predictors of treatment outcome. Methods: We used a machine Learning approach to assess a cohort of racially diverse 555 BC patients who underwent surgery for their primary BC in Greenville, NC and develop proteomics-based genomics (PbG) signatures. The cross-validated logistic regression modeling using publicly available gene expression data compiled from neoadjuvant clinical trials (N=996, JCO:30(16):1996-2004). Results: Kaiso and LC3A/B derived gene modules show accuracy in predicting pathological complete response (pCR, AUC = 0.728, 95% CI: 0.689-0.764). Moreover, predictive estimates of distant metastasis-free survival utilizing Kaiso and LC3A/B derived gene modules are also significant (overall DMFS, AUC= 0.737, 95% CI: 0.665-0.819) and (DMFS of non-pCR patients AUC= 0.71, 95% CI: 0.633-0.773). We then validate these findings in an independent, racially diverse breast cancer cohort receiving neoadjuvant treatment (N=443). Gene modules based on Kaiso and LC3A/B were also highly predictive in this independent cohort (total cohort pCR, AUC= 0.775, 95% CI: 0.687-0.838; pCR NHW (N=257), AUC= 0.762, 95% CI: 0.659-0.855; pCR Hispanic (N=125), AUC= 0.725, 95% CI: 0.493-0.873; and pCR NHB (N=42), AUC= 0.681, 95% CI:0.405-0.904). Conclusions: Combined analysis by multiplex immunofluorescence and deconvolution of gene expression data show that the protein expression of Kaiso and LC3A/B in tumors are associated with distinct tumor ecosystems where high levels cytoplasmic Kaiso are linked to an immune-suppressed tumor microenvironment.
Phase II randomized window of opportunity trial evaluating cytotoxic and immunomodulatory effects of intratumoral INT230-6 in early stage breast cancer: The INVINCIBLE trial.
Authors: Spears Melanie , Hopkins Megan , Keyhanian Kianoosh , Robertson Susan , Liao Linda , Talebian Vida , Awan Arif Ali , Pond Gregory Russell , Bartlett John , Bender Lewis H. , Walters Ian B. , Lopez-Ozuna Vanessa , Arnaout Angel 
Published: June 2023

573 Background: Most breast cancers are considered immunological cold and are therefore minimally responsive to immunotherapies. Local cytotoxic therapies can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. We conducted a randomized, double blind, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trialNCT04781725. The trial evaluated the immune response within the tumor and microenvironment in vivo after IT INT230-6 injections. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade ER+ T1-T2 invasive breast cancers were recruited to the trial. Participating patients were allocated (2:1) to IT injections of INT230-6 vs saline placebo, prior to resection. RNA profiling of the pre- (baseline biopsy) and post- treatment (surgical resection) tumours using the Ion AmpliSeq Transcriptome Human Gene Expression (Thermo Fisher Scientific) and DNA sequencing using a large (500 gene) comprehensive genomic profiling panel (OCAPlus,) was performed. Results: Significant tumor necrosis was observed in the majority of subjects injected with INT230-6. In the 60 pre-treatment biopsies profiled with OCAPlus, the genes most frequently mutated included PIK3CA (38%), TP53 (23%), CDH1 (22%) and TBX3 (17%). Frequent copy number changes were identified in CCND1 (23%), FGFR1 (18%), and CDH1 (17%). Gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens in patients treated with the drug. Pathway analysis identified genes associated with TCR signaling, macrophage markers, IL-18 signaling and B cell receptor signaling were significantly up-regulated in the post treatment samples. Conclusions: This is the first study evaluating the potential biologic effects of intratumoral cytotoxicity with INT230-6 and its role as a potential immune priming therapy in traditional immune quiescent ER+ breast cancers.
Treatment outcomes in patients with discordant recurrence score and RSClin risk predictions.
Authors: Vannier Augustin , Dhungana Asim , Zhao Fangyuan , Chen Nan , Shubeck Sarah , Hahn Olwen Mary , Nanda Rita , Jaskowiak Nora T. , Fleming Gini F. , Olopade Olufunmilayo I. , Pearson Alexander T. , Huo Dezheng , Howard Frederick Matthew 
Published: June 2023

574 Background: Guidelines recommend the use of genomic assays to aid decision making regarding the use of adjuvant chemotherapy (CT) for hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (EBC). Recently, the RSClin tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was developed to better estimate CT benefit. Here, we studied patients with RSClin/RS discordance to determine if patients (pts) should be treated according to RS or RSClin. Methods: This was a retrospective cohort study of pts from the National Cancer Database who were diagnosed with HR+/HER2- node negative EBC from 2010-2020 who underwent RS testing and received adjuvant endocrine therapy with or without CT. Pts were classified as low RS ( < 26) or high RS (≥ 26) and low ( < 3%) versus high (≥ 3%) predicted CT benefit per RSClin. The primary outcome was overall survival (OS) benefit associated with CT administration for pts with discordant RS/RSClin, measured as hazard ratio [HR] for receipt of CT. Hazard ratios were adjusted for age and comorbidity index, and inverse probability of treatment weighting was performed for age, comorbidity index, race, ethnicity, and insurance status. Results: 262,748 pts with EBC were included, with a median follow-up of 58 months. Median age was 60 years; 82% were White, 7% Black, 5% Hispanic, and 4% Asian/Pacific Islander. Median tumor size was 1.5 cm, and median RS was 15. The 31,955 cases with concordant high RS/RSClin had an OS benefit with CT (HR: 0.71, 95% CI: 0.67 - 0.75, p < 0.001), while the 206,631 cases with concordant low RS/RSClin did not have a survival benefit (HR: 1.00, 95% CI: 0.95 - 1.04, p = 0.85, Table). High RS with low RSClin was seen in 435 cases – all with grade 1 tumors, with RS no greater than 28, and tumor size under 1.3cm. No significant CT benefit was seen in this small subset of pts (HR 1.57, 95% CI 0.75 – 3.26, p = 0.23). In 23,727 pts with low RS but high RSClin, a CT benefit was seen (HR 0.73, 95% CI 0.67 – 0.78, p < 0.001). These pts had high-intermediate RS (median 23, interquartile range 20 – 24) with other higher risk features. Similar results were seen in older (age > 50) and younger (age ≤ 50) subgroups – although no pts ≤ 50 were in the low RS/high RSClin group. Conclusions: RSClin may identify a small number of grade 1 tumors with high RS for which CT is not needed, and may help guide appropriate use of CT for EBC in the sizeable group with intermediate RS. [Table: see text]
Assessment of the differential profile of breast intratumoral bacteria in treatment responders and nonresponders.
Authors: Basgaran Amedra , Lymberopoulos Eva , Paschke Sophie , Hobbs Michael , Alomari Muhannad , Sharma Nikhil 
Published: June 2023

580 Background: Despite improvements in breast cancer therapy, many patients do not respond to treatment: the response rate varies between 31 and 80% [Walks et al., 2019]. The tumor microenvironment contains a microbiome which is both cancer type-specific and different to surrounding normal tissue [Nejman et al., 2020]. It plays an important role in tumour microenvironment crosstalk with tumor cells and has been implicated in disease pathogenesis, being recognised in the latest hallmarks of cancer [Hanahan et Weinberg, 2011]. It has also successfully predicted treatment response [Chen et al., 2022; Hermida et al., 2022]. Here, we use conventional microbiome analysis alongside our proprietary mechanistically-powered technology platform to compare the intratumoral bacteria between responders and non-responders. We hypothesise that there are significant differences between those groups regarding composition and mechanistic function of the bacteria. Methods: The tumor microbiome can be deduced from existing sequencing data of tumor biopsy samples. Using 34 tumor DNA samples from 5 breast cancer studies, we compared the intratumoral bacterial profiles of responders to non-responders of various treatments. We performed microbiome analysis in R, including alpha diversity, compositional abundance profiles, and PERMANOVA (permutational analysis of variance). Additionally, BioCorteX CarbonMirror version dated 2023-02-14 was used to infer mechanistic links between bacterial species and the up- and downregulation of genes implicated in the hallmarks of cancer. Results: The results show significant differences in diversity and compositional profile between responders and non-responders: Non-responders have significantly higher alpha diversity ( p<0.05) and a higher proportion of Proteobacteria. PERMANOVA analysis revealed that while responders are more likely to have commensal bacteria, non-responder tumour microbiomes are more likely to harbor pathogenic species such as Mycoplasmopsis fermentans. Mechanistic analysis showed that for all responders the tumor microbiome is consistently promoting tumor suppressor genes and downregulating proto-oncogenes. In non-responders, however, the tumor microbiome is upregulating and downregulating both with unclear consistency. Conclusions: Our results show microbiome differences between responders and non-responders which were mechanistically implicated in tumor pathogenesis. Further analysis divided by the hallmarks of cancer is required to fully understand the non-responder microbiome links. The reported findings could make the tumor microbiome a useful biomarker aiding patient stratification for both prognosis and treatment choice. They also highlight a potentially meaningful mechanistic link between tumour microenvironment and treatment response that could be leveraged as a novel therapeutic avenue.
Effect of tumor microenvironment on chemotherapy response of patients with triple-negative breast cancer receiving neoadjuvant chemotherapy.
Authors: Kim Jae-Joon , Kim Dongjin , Yu Yeuni , Jung Ki Sun , Kim Yun Hak 
Published: June 2023

590 Background: Triple-negative breast cancer (TNBC) is a breast cancer subtype that has poor prognosis and exhibits a unique tumor microenvironment, including the corresponding immunological environment. Analysis of the tumor microbiome has indicated a relationship between the tumor microenvironment and treatment response. Therefore, we attempted to reveal the role of the tumor microbiome in patients with TNBC that were receiving neoadjuvant chemotherapy. Methods: We collected TNBC patient RNA-seq samples from the Gene Expression Omnibus (GEO; n of pathological complete response [pCR] = 38, n of residual disease [RD] = 50) and extracted microbiome count data using Kraken2 and Bracken. Differential and relative abundance were estimated with linear discriminant analysis effect size (LEfSe). We calculated the immune cell fraction with CIBERSORTx and conducted survival analysis using the Cancer Genome Atlas patient data (n = 115). Correlations between the microbiome and immune cell compositions were analyzed and a prediction model was constructed to estimate drug response using random forest (RF) and support vector machine (SVM). Results: Among the drug response group, the beta diversity varied considerably; consequently, 20 genera and 24 species were observed to express a significant differential and relative abundance using LEfSe analysis. The drug response prediction model accuracy exhibited 76.47 and 88.24 percent in RF and SVM, respectively; specifically, Pandoraea pulmonicola and Brucella melitensis were found to be important features in determining drug response. In correlation analysis, Geosporobacter ferrireducens, Streptococcus sanguinis, and resting natural killer cells were the most correlated factors in the pCR group, whereas Nitrosospira briensis, Plantactinospora sp. BC1, and regulatory T cells (Tregs) were key features in the RD group. Further, M2 macrophages and Brucella showed significant differences in survival between the pCR and RD groups (p < 0.05). Conclusions: Our study demonstrated that the microbiome analysis of tumor tissue can predict chemotherapy response of patients with TNBC receiving neoadjuvant chemotherapy. Further, the immunological tumor microenvironment may be impacted by the tumor microbiome, thereby affecting the corresponding survival and treatment response.