bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring molecular profiles of uterine carcinosarcoma with alterations in the chromatin remodeling pathway.
Authors: Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Rocconi Rodney Paul , Erickson Britt Kristina , Klc Tenley , Lesnock Jamie Lee , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Korn Wolfgang Michael , Powell Matthew A. , Jones Nathaniel L. 
Published: June 2021

5587 Background: In a preliminary data analysis to identify prognostic molecular biomarkers in uterine carcinosarcoma (UCS), we found that alterations in KMT2C, a gene involved in the chromatin remodeling pathway, correlated with improved survival. We sought to explore relevant biomarkers of KMT2C-mutated (KMT2C-mut) tumors compared to wildtype (KMT2C-wt) tumors. Methods: Tumor samples were analyzed using next generation sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). Microsatelite instability (MSI) was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: Molecular analysis was performed on 1,144 UCS tumors. 7.7% were found to be KMT2C-mut. Patients with pathogenic alterations in KMT2C had longer median OS than patients without (OS not yet reached vs 19.0 months HR(95% CI): 0.37(0.19-0.72) p< 0.01). The most common mutations in KMT2C-mut tumors are shown in Table and resulted in more frequent dysregulation in the following pathways compared to KMT2C-wt tumors: chromatin remodeling (100% vs 28%; q<0.01), WNT (39% vs 12%; q=0.01), base/nucleotide excision repair (29% vs 5%; q<0.01), homologous recombination (26% vs 6%; q=0.02), DNA damage sensors (23% vs 4%; q=0.02) and Fanconi anemia (13% vs 1%; q=0.04). KMT2C-mut tumors were more frequently MSI-H (32% vs 6%; q<0.01) and TMB-H (42% vs 5%; q<0.01). Among MSS tumors, KMT2C-mut tumors had increased mutations in JAK1 and POLE (q<0.01) and higher frequency of TMB-H (24% vs 1%; q<0.01) than KMT2C-wt tumors. Additionally, MSS patients with KMT2C-mut had longer OS than patients with KMT2C-wt tumors (OS not yet reached vs 18.9 months; HR(95% CI): 0.33(0.15-0.75) p< 0.01). Conclusions: Mutations in KMT2C correlate with improved OS in UCS. KMT2C-mut tumors have distinct molecular profiles from wild type tumors. They exhibit greater immunogenicity, including more frequent MSI-H and TMB-H. This suggests a potential role for Immune-oncology (IO) therapy. Further study of the impact of IO therapies in the cohort is warranted as this may contribute to the improved survival of these patients.[Table: see text]
Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.
Authors: Jones Nathaniel L. , Wu Sharon , Xiu Joanne , Craig Amaranta , Mantia-Smaldone Gina , Hernandez Enrique , Rocconi Rodney Paul , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Korn Wolfgang Michael , Powell Matthew A. , Wilhite Annelise M. 
Published: June 2021

5590 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be < 0.05. Results: Molecular analysis was performed on 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p < 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.
Association of allograft rejection response score with biological cancer aggressiveness and with better survival in triple-negative breast cancer (TNBC).
Authors: Oshi Masanori , Le Lan , Angarita Fernando A , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki 
Published: June 2021

561 Background: Although the importance of immunity in the progression of breast cancer was widely reported, the clinical relevance of enhanced immune response is still unclear. We hypothesized that the enhanced immune response is associated with better breast cancer patient survival. Methods: We used 6,245 breast cancer patient sample data from publicly available data sets (METABRIC, GSE96058, TCGA cohorts). To elucidate the function of immunity in breast cancer, we calculated the immune function score using hallmark allograft rejection gene sets by Gene Set Variation Analysis algorithm. Results: The immune response score correlated most with cytolytic activity among hallmark immune-related gene sets in both cohorts (Spearman’s rank correlation (r) = 0.892 and 0.860, respectively, both p < 0.01). The score reflected the amount of infiltrating immune cells, including several anti-cancer immune cells (CD8+ T cells, CD4+ memory T-cells, T helper Type 1 cells, M1 macrophages, plasmacytoid dendritic cells), T helper Type 2 cells, and B cells. The score also correlated with expression levels of immune checkpoint molecule genes (all r > 0.500). A high score was significantly associated with high intratumor heterogeneity, homologous recombination deficiency (HRD), and mutation rate in the TCGA cohort (all p < 0.001). A high score was significantly associated with advanced Nottingham histological grade, advanced stage, and lymph node metastasis. High score breast cancer enriched not only immune-related gene sets but also pro-cancer-related gene sets, such as epithelial-mesenchymal transition (EMT) and p53 pathway, in both ER-positive/HER2-negative breast cancer and TNBC. The score was highest in TNBC compared to other subtypes, and TNBC with high score was significantly associated with better survival. Conclusions: The counterbalance between malignant biology and the enhanced immune response is an important factor in clinical outcomes.
Survival in male breast cancer (MaBC) over the past three decades.
Authors: Leone Jose Pablo , Freedman Rachel A. , Leone Julieta , Hassett Michael J. , Tolaney Sara M. , Vallejo Carlos Teodoro , Leone Bernardo Amadeo , Winer Eric P. , Lin Nancy U. 
Published: June 2021

569 Background: Breast cancer mortality in women has declined significantly over the past several years. In men, it is unclear whether survival has changed over time. The aim of this study was to evaluate changes in breast cancer-specific survival (BCSS) and overall survival (OS) in MaBC over the past three decades. Methods: We evaluated men diagnosed with breast cancer between 1988 and 2017, with known cause of death reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007 and 2008-2017. BCSS and OS were estimated by Kaplan-Meier and differences between groups were compared by log-rank test. Cox proportional hazards regression was used to evaluate the independent association of tumor and patient characteristics with BCSS and OS. Results: We included 8,412 men diagnosed between 1988-1997 (N = 1,033), 1998-2007 (N = 2,938) and 2008-2017 (N = 4,441). Median age for the overall population and within each decade of diagnosis was 68 years. Median follow-up was 23.6 years, 14.3 years and 4.5 years in periods 1988-1997, 1998-2007 and 2008-2017, respectively. Overall, BCSS at 5 years was 83.5%, 83.6% and 84.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.8. There was no significant difference in BCSS between the three periods of diagnosis within each stage of breast cancer (stage I, II, III and IV). Among all patients, OS at 5 years was 64.7%, 67.2% and 69.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.01. In multivariate Cox models, older age at diagnosis, black race, grade 3 disease, increasing stage, hormone receptor negative status and no surgery were all independently associated with worse BCSS and OS. In these adjusted Cox models, each additional year of diagnosis had no significant association with BCSS (hazard ratio, 1.0; 95% CI, 0.99 – 1.01; p = 0.78), and a significant improvement in OS (hazard ratio, 0.99; 95% CI, 0.98 – 0.99; p = 0.01). Conclusions: Over the past three decades, there has been no significant improvement in BCSS in MaBC. The changes in OS over time suggest increasing life expectancy. Efforts to improve BCSS in MaBC are warranted.
Automated, IHC/FISH-free, H&E histopathology image-based HER2 amplification, tumor infiltrating lymphocyte (TIL) and tumor heterogeneity profiling in breast cancer.
Authors: Mukhopadhyay Satabhisa , Dasgupta Tathagata , Orsi Nicolas M , Cummings Michele , Berwick Angelene 
Published: June 2021

593 Background: Digital pathology has fostered the development of automated diagnostic solutions. However, current technologies in breast cancer remain unable to determine HER2 amplification status, which is established by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). These ancillary tests carry a significant cost, prolong diagnostic time and fail to capture HER2 tumor heterogeneity and tumor infiltrating lymphocyte (TIL) burden, both of which determine the effectiveness anti-HER2 targeted therapy. Methods: This study describes the real-life clinical context development and validation of a patented novel, universal, automated, white-box, scanning platform agnostic solution that determines HER2 amplification status, prognostically significant TIL levels and tumor heterogeneity index (HI) from hematoxylin and eosin (H&E) stained malignant breast biopsy whole slide images (WSIs) alone. Unlike conventional artificial intelligence-based approaches, the underlying proprietary algorithm’s prediction criteria are explainable and are based on deterministic, hard-coded observational relationships of scale constructed from image morphological features mapped to observables representing underlying tumor-related perturbations in biological pathways/mitotic checkpoints.This includes G1/S deregulation signatures reflecting oncogenic HER2-neu. Results: Blinded validation of HER2 status prediction (n = 197 WSIs; 118 independent cases/patients) showed excellent diagnostic performance (κ = 0.85) relative to existing standard-of-care methodologies. This was independent of WSI file format, background histology, tumor subtype/grade or hormone receptor status. The device also displayed good accuracy (92%) in determining TIL profiles, and its combined HER2-TIL and HER2-HI prediction scales both exhibited a significant association with progression-free survival (CoxPH hazard ratio: 1.856; 95% CI: 1.002-3.438; p = 0.049 and CoxPH hazard ratio: 3.45; 95% CI: 0.95-12.55; p = 0.060). Conclusions: This technology opens up the future possibility of bypassing existing ancillary HER2 profiling investigations, thus potentially reducing laboratory workloads/healthcare costs while accelerating diagnostic turnaround times for patient benefit. In the interim, if used as an adjunct tool, this device could provide an objective HER2 testing reference scale while the robustness of its prediction of patient response to anti-HER2 targeted therapy is fully explored.
Phase II trial of soluble EphB4-albumin in combination with PD-1 antibody (pembrolizumab) in relapsed/refractory head neck squamous cell carcinoma.
Authors: Jackovich Alexandra , Gitlitz Barbara J. , Tiu-lim Justin Wayne Wong , Duddalwar Vinay , King Kevin George , El-Khoueiry Anthony B. , Thomas Jacob Stephen , Tsao-Wei Denice , Quinn David I. , Gill Parkash S. , Nieva Jorge J. 
Published: June 2021

6016 Background: EphB4 receptor tyrosine kinase and its ligand EphrinB2 are highly induced in head neck squamous cell carcinoma (HN SCC) tumor cells and vessels, particularly in HPV negative tumors. Each are predictors for poor survival with worse prognosis when both are induced. EphB4 provides tumor cell survival and EphrinB2 inhibits immune cell invasion. Soluble EphB4-Alb blocks bidirectional signaling, enhances immune cell recruitment alone and when combined with PD-1 antibody. Methods: A phase II trial of sEphB4-Alb combined with pembrolizumab accrued HN SCC patients after failure of one or more prior regimens. IHC positivity for p16 was used as a surrogate for HPV infection. Treatment regimen was sEphB4-Alb 10 mg/kg weekly IV infusion with pembrolizumab 200 mg IV infusion every three weeks. Study endpoints were toxicity, overall response rates (ORR) and overall survival (OS). Response to therapy was based on RECIST 1.1 criteria. Patient tumor samples were collected at baseline with a 2nd biopsy at week 8 on therapy, for tissue analysis of PD-L1, EphrinB2 and other biomarkers. Results: Twenty-four patients were accrued to the phase II trial combination of sEphB4-Alb and pembrolizumab. Age, sex, prior treatment, HPV status, and response data are summarized in the table below. The most common toxicity was hypertension with 8 patients experiencing grade 3 HTN. No grade 4 or above toxicities were observed. Among HPV negative cases, partial and complete responses were observed in 6 of 14 patients (43%) with complete response (CR) observed in 3 of 6 responders. Additionally, rapid response was observed in 3 of 14 HPV negative patients. Response was associated with increase in immune markers on 2nd biopsy. Median overall and progression-free survival in all patients was 12.6 months and 8.6 months, respectively. Conclusions: 1. sEphB4-Alb was well tolerated in combination with PD-1 antibody. 2. sEphB4-Alb was associated with increased immune response to tumor, when combined with PD-1 antibody. 3. sEphB4-Alb appears to have substantial activity (including complete remission) when combined with PD-1 antibody in relapsed/refractory HPV negative HN SCC. Clinical trial information: NCT03049618. [Table: see text]
Long-term follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Cho Byoung Chul , Daste Amaury , Ravaud Alain , Salas Sébastien , Isambert Nicolas , McClay Edward Francis , Awada Ahmad , Borel Christian , Helwig Christoph , Rolfe P. Alexander , Ojalvo Laureen S. , Gulley James L. , Penel Nicolas 
Published: June 2021

6020 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. A previous report of an expansion cohort from a phase 1 study (NCT02517398) suggested that bintrafusp alfa had a manageable safety profile and early signs of clinical activity in patients with heavily pretreated, advanced SCCHN after a median follow-up of 86.4 weeks. Here we report long-term efficacy and safety for this cohort. Methods: Patients with advanced SCCHN that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or < 6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg every 2 weeks until confirmed progressive disease, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response assessed per RECIST 1.1 assessed by independent review committee (IRC); safety was a secondary endpoint. Results: As of May 15, 2020, 32 patients had received bintrafusp alfa for a median of 2.8 months (range, 0.5-29.9 months), no patient remained on treatment, and median follow-up to data cutoff was 41.7 months (range, 39.8-43.5 months). The objective response rate (ORR; 13%) was unchanged since the previous report; median duration of response (DOR) was increased at 21.4 months (95% CI, 5.5 months to not reached [NR]). While the clinical activity of bintrafusp alfa may be improved in patients with HPV-positive tumors (Table), outcomes were generally similar between PD-L1 subgroups (≥1% vs < 1% tumor cells). The overall safety profile was consistent with the previous report for this cohort, without grade 4 nor 5 treatment-related adverse events (TRAEs); no new TRAEs of grade 3 or that led to discontinuation of bintrafusp alfa were reported. Conclusions: With a median follow-up of over 3 years in patients with heavily pretreated advanced SCCHN, bintrafusp alfa showed sustained clinical activity and 3-year OS of 24.0%, which compares favorably to historical data. Clinical activity appeared to be greater in patients with HPV-positive tumors than those with HPV-negative tumors. The safety profile was manageable and consistent with earlier analysis. Further investigation of bintrafusp alfa in SCCHN and other HPV-associated cancers is ongoing. Clinical trial information: NCT02517398. [Table: see text]
Maintenance intervention to improve survival in patients with metastatic nasopharyngeal carcinoma who benefit from first-line treatment: A prospective multicenter randomized controlled clinical study.
Authors: Lu Ying , Huang Haixin , Yang Hui , Hu Xiaohua , Feng Xianbing , Huang Changjie 
Published: June 2021

6035 Background: The role of drug maintenance intervention in improving survival outcomes remains controversial.To investigate the safety and effect of Tegafur(S1) maintenance intervention in patients with metastatic nasopharyngeal carcinoma who benefit from the first-line treatment in a multicenter randomized controlled study, and to identify the related biological prognostic factors and guide the individualized treatment choice. Methods: Patients with metastatic nasopharyngeal carcinoma in the Fourth Affiliated Hospital of Guangxi Medical University and other cancer centers who met the inclusion criteria were randomly divided into maintenance therapy group: S1 maintenance therapy until disease progression or intolerance; Observation group: follow-up to disease progression. PFS, overall survival (OS) and adverse reactions of S1 maintenance therapy were compared between the two groups. The correlation between EBV-DNA, human serum amyloid A (SAA) and prognosis was evaluated. Results: Follow-up was conducted to May 2020, with a median follow-up of 19.8 months (6.1-51.3 months), 183 cases were evaluable (88 cases in S1 maintenance treatment group, 95 cases in observation group). Compared with the observation group, the S1 maintenance treatment group significantly increased patients' median PFS (16.2 months vs. 8.7 months, P < 0.001) and median OS (32.1 months vs. 18.2 months, P < 0.001). Reduced the risk of poor prognosis for PFS and OS (PFS: HR 0.305, 95%CI 0.211-0.441, < 0.001; OS: HR 0.363, 95%CI 0.238-0.553, P < 0.001). In the maintenance treatment group, the median S1 treatment lasted for 14 courses (4-58 courses), and the main adverse reactions were grade 1 skin pigmentation, oral mucositis, hand-foot syndrome, nausea, etc. No grade 4 toxic reaction occurred, and it was well tolerated. Compared with observation patients with negative EBV-DNA, observation patients with positive EBV-DNA had a higher risk of poor prognosis for PFS (HR 1.764, 95%CI 1.078-2.887, P = 0.024). The risk of poor prognosis in patients with positive EBV-NDA was significantly reduced by 61.1% ( < 0.001) for PFS and 65.5% (P = 0.001) for OS (P = 0.001). Compared with the observation group with stable SAA expression, S1 maintenance therapy significantly improved the prognosis of patients. Patients with continuous decline in SAA had a 61.9% lower risk of poor prognosis in PFS (P < 0.001) and a 60.2% lower risk of poor prognosis in OS (P = 0.007). Conclusions: For patients with metastatic nasopharyngeal carcinoma who benefit from first-line treatment, maintenance therapy of S1 can significantly improve the survival prognosis and is well tolerated. Patients with positive EBV-DNA and continuous decline in SAA may benefit more from maintenance intervention. Clinical trial information: ChiCTR-IOR-16007939.