bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-6 blockade for prophylaxis and management of immune-related adverse events (irAEs) with anti-PD-1 based immunotherapy.
Authors: Dimitriou Florentia , Hogan Sabrina A , Cheng Phil F , Dummer Reinhard , Menzies Alexander M. , Long Georgina V. 
Published: June 2021

9553 Background: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory irAEs. We sought to determine the activity of tocilizumab, an anti-IL6R monoclonal antibody (mAb), in treatment or prevention of auto-immune irAE in ICI-treated patients (pts). Methods: Institutional databases from 2 melanoma centers were reviewed for pts treated with ICIs and tocilizumab. Treatment and melanoma outcomes were prospectively assessed. Longitudinal assessment of c-reactive protein (CRP) and assessment of clinical improvement (defined as irAE resolution to grade ≤1 CTCAEv5) or prophylaxis (absence of flare, defined as ≥ grade 2) were utilized to evaluate the benefit of tocilizumab. Paired Wilcoxon rank test was used to compare CRP levels prior to ICI administration, at the onset of irAEs and after tocilizumab administration. Results: 22 pts were identified. 2 pts were treated prophylactically (pre-existing dermatomyositis [n = 1] and giant cell arteritis [GCA, n = 1]) before the administration of PD1. 20 pts were treated for management of irAEs due to PD1 +/-CTLA4 (multiple concurrent irAEs [n = 3], steroid refractory irAES [hepatitis & pancreatitis, n = 2], steroid+anti-TNFα refractory colitis [n = 2], steroid+other immunosuppressive-refractory hepatitis [n = 1], cytokine release syndrome-related AEs [n = 6], musculoskeletal irAEs [n = 6]). 15 (68.2%) pts with irAEs required hospitalization and of those, 13 (86.7%) received tocilizumab whilst inpatient. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab administration 32 days (range 1-192). Median time to irAE resolution from tocilizumab administration was 7 days (range 1-799). Clinical improvement/benefit was demonstrated in 21/22 patients; one patient with ir-hepatitis did not respond. Median CRP prior to ICI administration was 32mg/L (range 0.3-99), at the onset of irAE 49.5mg/L (range 0.3-251, p = 0.055) and after the tocilizumab administration 18mg/L (range 0.3-18, p = 0.0015). Tocilizumab was well tolerated with self-limiting and transient toxicities in 17 (77.3%) patients. There were two grade 4 events; gastrointestinal tract perforation and Fournier gangrene, the latter unrelated to tocilizumab. Two (9%) patients died due to melanoma. From start of ICI, median progression-free survival (PFS) was 5.88 months and median overall survival (OS) was not reached. Conclusions: Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of a flare of pre-existing auto-immune disorders during ICI administration. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
Outcomes of non-treatment naive melanoma patients with central nervous system relapse.
Authors: Pimentel Muniz Thiago , Lone Hadee , Arteaga Diana Paola , Gray Diana , Silveira Vilbert Pereira Maysa Tamara , Mantle Luke , Singh Raviya , Genta Sofia , Saibil Samuel , Hogg David , Spreafico Anna , Butler Marcus O. 
Published: June 2021

9557 Background: Melanoma has a high probability of central nervous system (CNS) spread. Although first line nivolumab and ipilimumab resulted in 56% response rate and 29.2 months median overall survival (OS) in patients with melanoma brain metastases (MBM), there is paucity of data for patients who develop MBM after prior systemic therapy. As this subgroup is often underrepresented in clinical trials, we aimed to evaluate the OS of non-treatment naïve patients who develop MBM and identify factors related to survival. Methods: In this single-center, retrospective study, consecutive melanoma patients with > 90 days from exposure to either immune checkpoint inhibitor (ICI), targeted therapy (TT), or chemotherapy, to CNS relapse were included. OS was defined as the time between CNS relapse and death by any cause. The Log-Rank method was used to calculate OS. Cox regression analysis was used to identify differences between subgroups. Variables with a p value < 0.1 were included in a multivariate model. A p value < 0.05 was considered statistically significant. Results: Between 2012 and 2018, 135 patients were identified. Median age was 57 (29-92) years, 92 (68%) were male, and median number of prior systemic therapies was 2 (1-6). One-hundred and nine (81%) patients had cutaneous melanoma; acral lentiginous melanoma (ALM) comprised 11 (8%) patients. Molecular studies were available for 123 patients, of whom 61 (50%) were BRAF V600 mutant. Eighty-nine (66%) patients had prior ICI, of whom 33 (37%) had prior exposure to both anti-PD1 and anti-CTLA-4, either as monotherapy or combination. Amongst the BRAF V600 mutant population, 48 (79%) had prior TT. Radiotherapy was given to 112 patients, of whom 55 (49%) had SRS. Median follow-up was 41 (95% CI 30-51) months. Median OS was 6.4 (95% CI 5.3-7.5) months. Patients with ALM, > 3 MBM, ECOG 2-4 and active treatment at CNS relapse (< 30 days from last dose of treatment to MBM diagnosis) were at increased risk of death, whilst subsequent treatment with ICI was related to better survival (Table). On multivariate analyses, age ( p = 0.007), subtype ( p = 0.04), number of MBM ( p = 0.01), active treatment at CNS relapse ( p < 0.001) and subsequent ICI ( p = 0.002) remained statistically significant. Exploratory analyses suggested subsequent treatment with anti-PD1 + anti-CTLA-4 (n = 42) compared favourably to subsequent anti-CTLA-4 only (n = 21) (13 x 7 months, p = 0.004), and was independent of prior ICI. Conclusions: Previously treated melanoma patients who develop MBM have a poor prognosis, but subsequent ICI therapy seems to be associated with better OS. Further clinical investigation to identify optimal anti-PD1-based therapies is warranted for non-treatment naïve patients who develop MBM.[Table: see text]
Association between estrogen receptor status and Oncotype Dx breast recurrence score.
Authors: Khan Noman Ahmed Jang , Abdallah Mahmoud , Gress Todd W. , Alsharedi Mohamed Farouq 
Published: June 2021

e12519 Background: The 21 gene assay Oncotype Dx Breast Recurrence Score (RS) is currently the standard of care to determine if adjuvant chemotherapy is needed in early stage node negative, hormone receptor positive, HER-2 negative breast cancer. In current American society of clinical oncology (ASCO) guidelines there is little or no benefit of adjuvant chemotherapy in patients older than 50 years whose tumors have Oncotype DX RS <26, and for patients 50 years or less whose tumors have Oncotype DX RS <16. We sought to evaluate the percentage of estrogen receptor (ER) expression as a surrogate measure of determining adjuvant chemotherapy by examining the relationship between ER expression and RS. Methods: We identified 301 patients from years 2015 to 2019 from our cancer registry with early stage hormone receptor positive breast cancer and had oncotype DX testing performed. We divided patients into three groups: Group 1 (ERG1) with ER <10%; Group 2 (ERG2) with ER 10-49%; and Group 3 (ERG3) with ER equal or >50%. We also collected information on tumor size (cm), tumor grade, Nottingham score, and ki-67 percentage. A sub-group analysis was performed for patients < 50 years age (n=30). We compared all continuous variables across ER groups using the Kruskal-Wallis rank test and individual between group comparisons using the Wilcoxon rank sum test. All statistical tests performed utilized a two-tailed p value of <0.05 with the Bonferroni correction for multiple comparisons. Results: Among 301 patients with early stage hormone receptor positive breast cancer, 89.1% were ductal, 7.9% lobular, and 2.9% mixed histology. Median age was 68, 58 and 66 for ERG1, ERG2, and ERG3, respectively (p = 0.41). Median RS was 36 (ERG1), 23 (ERG2), and 16 (ERG3) (p = 0.78 for ERG1 vs. ERG2; p = 0.01 for ERG1 vs. ERG3). As expected, tumor grade, tumor size, and Nottingham score decreased significantly from ERG1 to ERG3. For patients <50 years, median age was 44, 46 and 45 for ERG1, ERG2, and ERG3, respectively (p = 0.75). Median RS was 10 (ERG1), 24 (ERG2) and 18 (ERG3) (p = 0.04 for ERG1 vs. ERG2; p = 0.17 for ERG1 vs. ERG3). Conclusions: We found a significant association between estrogen receptor levels and Oncotype Dx recurrence score (RS) in patients with early stage hormone receptor positive breast cancer patients. Further studies are needed to determine the predictive ability of hormone receptor levels on the outcomes of patients treated for early stage hormone receptor positive breast cancer.
The role of C-reactive protein (CRP) as a prognostic biomarker in patients with early breast cancer (EBC) treated with neoadjuvant chemotherapy (NACT).
Authors: Kolberg Hans-Christian , Edimiris Alexandra , Hoffmann Oliver , Wetzig Sarah , Shaheen Mohamed , Stephanou Miltiades , Kolberg-Liedtke Cornelia 
Published: June 2021

e12545 Background: C-reactive protein (CRP) is an acute phase reactant influenced by inflammation and tissue damage. It has been demonstrated that elevated CRP levels are associated with poor outcome of cancer including metastatic breast cancer. However, evidence regarding an impact of CRP levels on outcome in early breast cancer (EBC) are missing. Methods: Patients after neoadjuvant chemotherapy (NACT) for EBC and with available data regarding CRP levels before therapy, pathologic complete remission (pCR) and follow-up were included. The association between CRP at baseline and outcome parameters was analyzed. Results: 156 women were included in this analysis, median follow up was 5.8 years. No association between CRP at baseline and pCR rates could be detected. 6.4% of the patients developed a local recurrence, 10.3% developed a distant recurrence and 5.1% died from breast cancer. A negative correlation (Spearman-Rho) between CRP at baseline and overall survival (OS) (Correlation coefficient (CC) -0.255; p = 0.45), disease free survival (DFS)(CC -0.348; p = 0.075), local recurrence free survival (LRFS)(CC -0.245; p = 0.327) and distant disease free survival (DDFS)(CC -0.422; p = 0.057) was not statistically significant, although especially in DFS and DDFS a strong trend was detected. The probability of death from breast cancer was 2% if the CRP was < 0.08 mg/dl and 40% if the CRP was > 2.08 m/dl, this association was highly statistically significant (Chi Square; p < 0.001). These results were independent from age, estrogen and progesterone receptor status, HER2 status and grading. Conclusions: CRP at baseline is not predictive for pCR in EBC after NACT in our patient dataset. However, an association of parameters of long-term prognosis with CRP could be demonstrated. Although the correlations of higher CRP at baseline and shorter OS, DFS, LRFS and DDFS were not significant, a strong trend could be detected that was reproduced in the analysis of different cut-offs for CRP and the probability of breast cancer mortality. Higher CRP-levels are indicating a worse prognosis in early breast cancer after NACT in this retrospective analysis. These results justify further investigation of CRP as a biomarker of long-term prognosis in early breast cancer in prospective trials.
Association of triple negative breast cancer (TNBC) with high thermogenesis with worse survival and unfavorable tumor microenvironment (TME).
Authors: Gandhi Shipra , Oshi Masanori , Repasky Elizabeth A. , Takabe Kazuaki 
Published: June 2021

e12546 Background: Norepinephrine released during cold stress by housing 4T1 TNBC mice at 22°C increases tumor growth with a pro-tumorigenic TME [lower CD8+ T-cells, higher myeloid derived suppressor cells (MDSC) and regulatory T-cells (Treg)] compared with mice housed at 30°C. Norepinephrine activates thermogenesis in adipose tissue. Worse survival has been reported among females with malignancies living in cold versus warm climate. These findings led us to hypothesize that TNBC with enhanced thermogenesis is associated with worse outcome and unfavorable TME. Methods: mRNA expression data for 298 and 143 TNBC patients was accessed from METABRIC and GSE96058 breast cancer cohorts, respectively. TNBC were classified into “high” (top tertile) and “low” thermogenesis (bottom two-third) using Gene Set Variation Analysis (GSVA) with KEGG thermogenesis pathway. Computer algorithms xCell and Gene Set Enrichment Analysis (GSEA) were used. Interferon (IFN)-γ signature was calculated using GSVA. Gene expression data was used to quantify adipocytes, angiogenesis, chemokines and cytolytic activity (CYT). R software was used for analysis. False discovery rate (FDR) < 0.25 for GSEA and p < 0.05 was considered statistically significant. Results: High-thermogenesis TNBC was associated with a worse median disease specific survival 14.7 years vs. not reached [HR 1.49 (95% CI 1.02-2.18)], p < 0.05 in METABRIC and a trend towards worse overall survival in both METABRIC and GSE96058. Higher fraction of adipocytes (p < 0.001) and angiogenesis markers including CD31, vWF, Vascular endothelial cadherin, claudin 5, JAM2 and sphingosine-1-phosphate related gene S1PR1 (p < 0.01) were observed explaining the worse survival in high-thermogenesis TNBC. This group was significantly enriched in fatty acid metabolism and adipogenesis pathways (FDR < 0.25) on GSEA. On the other hand, low-thermogenesis TNBC was enriched in mitotic spindle, E2F targets, G2M checkpoint, MYC targets consistent with higher Ki67 (p < 0.05) in this group; and also in IFN-α and IFN-γ response (FDR < 0.25). High-thermogenesis TNBC was associated with lower IFN-γ and granzyme B expression (p < 0.05). Favorable cytotoxic-T cell attracting chemokines CCL5, CXCL9, CXCL10 and CXCL11 were lower; MDSC-, Treg-favoring chemokine CXCL12 was higher (p < 0.05). There were lower M1 and more M2 macrophages (p < 0.001) with lower CYT. There was higher expression of dual-specificity phosphatase-1 ( DUSP1)(p < 0.05), which is upregulated following glucocorticoid receptor activation. Conclusions: We investigated the clinical relevance of preclinical findings and observed that high-thermogenesis TNBC is associated with worse survival and unfavorable TME. Further research is warranted to validate if high thermogenesis could reflect tumors under thermal stress and develop novel strategies to abrogate stress and improve outcomes.
Gasdermin D as a potential prognosis and treatment response prediction biomarker for invasive breast cancer.
Authors: Xia Xianghou , Yin Wenjuan , Mao Jiefei , Hu Jiejie , Zou Dehong , Yang Hongjian , Yu Yang 
Published: June 2021

e12548 Background: Pyroptosis is a type of inflammatory cell death mediated by gasdermins. Pyroptosis is critical for macrophage against pathogen infection. Recently growing evidences show that pyroptosis may affect development and progression of many cancers. We aim to explore the expression and related function of pyroptosis executioner Gasdermin D (GSDMD) in breast cancer. Methods: We investigated the expression level of GSDMD using TNM plotter and Breast Cancer landscape proteome with TCGA, GTEx and TARGET databases, and the prognostic value of GSDMD in invasive breast cancer using Kaplan-Meier plotter with TCGA, GEO and EGA databases. The treatment response prediction values of GSDMD in invasive breast were calculated using ROC-plotter with GEO database. Further validation of the prognostic value and chemotherapy response prediction value of GSDMD were carried out with immunohistochemical staining on tissues from 165 cases of breast cancer patients receiving neoadjuvant chemotherapy in our cancer center. Results: TNM plotter and breast cancer landscape proteome portal analysis shows that overall expression level of GSDMD in invasive breast cancer tissue is 1.67 folds higher than it is in breast normal tissues ( p=1.05*e-06). Expression of GSDMD in LuminalB subtype (p=0.019) and Her2 subtype(p=0.04) is significantly higher than it is in TNBC subtype. Calculations with Kaplan-Meier plotter show expression of GSDMD is negatively correlated with overall survival(OS), HR=0.61(0.4−0.95) p=0.027 and relapse free survival (RFS), HR =0.65(0.58−0.63), p=8.7*e-14 and distant metastasis free survival (DMFS) HR =0.75(0.61−0.91), p=0.0038 in breast cancer patients. ROC-plotter calculations show high GSDMD expression is a powerful endocrine therapy (AUC=0.731 p=6*e-09 ) and chemotherapy response (AUC=0.64 p=8*e-05 ) predictor based on 5-year RFS in overall breast cancer patients. Our IHC staining analysis shows consistent prognostic and chemotherapy prediction value of GSDMD expression in TNBC patients. Conclusions: In conclusion, our findings suggest that high expression of GSDMD is positively correlated with prognosis and therapeutic response in breast cancer. GSDMD is a promising prognostic marker and therapeutic response predictor in invasive breast cancer.
Ki-67 and mitotic index in triple-positive breast cancer.
Authors: Urezkova Maria Mikhailovna , Semiglazova Tatiana , Artemyeva Anna , Kudaybergenova Asel 
Published: June 2021

e12551 Background: A grade in breast cancer is the strongest prognostic factor. In the new edition of the AJCC 8th, the tumor grade is one of the criteria that determines patients with breast cancer in the prognostic groups. According to the Nottingham system the mitotic count (MC) mostly determines the grade. Interobserver reproducibility for MC is not as good as for IHC marker phh3. The group of triple-positive breast cancer (TPBC) is characterized by the presence of a crosstalk mechanism between the signaling pathways of ER and HER2, which leads to the development of resistance to therapy. However, according to the 8th AJCC, patients with ER+/HER2+ belong to a more favorable prognostic group. Methods: We selected 284 patients with early BC who received treatment at our centre from 2012 to 2020 and didn’t receive presurgical therapy. The patients were divided according to the surrogate subtype into triple-positive (n = 90) and other subtypes (n = 194). The Ki-67, the number of nuclei of tumor cells stained with anti-phh3 antibody, the cell density of the tumor per 1 mm2 and the number of phh3 + per 1000 tumor cells were assessed. Results: Visually accessed number of mitoses was grade 3 in 30% of tumors in the TPBC group and 29% in the second group. There was no statistically significant difference in the Ki-67 index of proliferative activity in the two studied groups. In the TPBC group the median Ki-67 was 16.8%, in the second group - 18.3% (p = 0.376516), while the groups differed significantly in terms of the phh3 index (the median in the TPBC was 23.7/mm2, the median in the second group - 16.06/mm2, p = 0.024703). The groups also significantly differed in the number of nuclei of tumor cells that directly entered the mitotic phase (5.1/1000 nuclei in the TPBC group versus 3.2/1000 nuclei in the second group, p = 0.003901). Conclusions: Despite similar indices of proliferative activity in the TPBC and non-TPBC groups, mitotic activity and the number of directly dividing tumor cells in the TPBC group are significantly higher than in the rest of the BC population. Considering the criteria for assessing phh3 (MC 1 < 4/mm2, MC 2 2 4 to 7/mm2, MC 3 > 7/mm2), most TPBCs will have a histological malignancy grade of 3, which according to AJCC 8th places them in the group of poor outcome. We suggest that these differences may be due to the crosstalk mechanism. The second conclusion of our study is the fact that Ki-67 is a poor predictor of the MC.
Racial disparity in OncotypeDX score in early stage, hormone receptor positive, HER-2 negative, node negative breast cancers: A systemic review and meta-analysis.
Authors: Lee Yi , Liu Ruolin , Bean Alexis K. , Garshasebi Madison J. , Jehangir Qasim , Kaur Jasmeet , Krishnamoorthy Geetha , Goodman Judie R. 
Published: June 2021

e12555 Background: Oncotype DX Breast Recurrence Score (RS) is the currently used risk-assessment tool for early-stage, hormone receptor-positive, HER-2 negative, node-negative breast cancer in the US. Studies showed inconsistency in RS distribution and treatment among races. Causes may include variations in somatic mutations like Ki-67, which have been reported to express higher in African American (AA) and Asian populations than in Non-Hispanic White (NHW) population, germline mutations in BRCA and TP53, that are not in the RS algorithm, and financial burden of the testing. We analyzed data from different countries to investigate racial disparity in RS. Methods: We searched Medline, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials, indexed from January 2010 to January 2021. More than 85% of studies were conducted in the pre-TAILORx study phase. To include data that are available and better represent different races, we included studies that used the previous cutoff value, low-risk ( < 18), intermediate-risk (18-30), high-risk ( > 30). Retrospective studies using Surveillance, Epidemiology, and End Results or National Cancer Database were excluded to avoid overlap data. A total of 17 studies, 9789 patients from seven countries (US, Japan, China, Taiwan, Kuwait, UAE, Israel) were pooled. The Odds Ratio (OR) was extracted with a 95% confidence interval (CI) for RS distribution and post-RS treatment. Both fixed-effect and random-effect meta-analysis were performed. Results: Among AA and NHW, AA were 1.7 times more likely to have high recurrence score (OR = 1.75; 95% CI = 1.46 - 2.10; P < 0.0001), with no heterogeneity among studies (I2 = 0%, heterogeneity P = 0.59). Asian were 1.59 more likely than NHW to be high-risk using a random effects model (OR = 1.59; 95% CI = 1.06 - 2.40; P = 0.0259). High-risk Asian were two times more likely to receive adjuvant chemotherapy post-RS comparing to NHW (OR: 2.31, CI: 1.07 - 4.98, fixed effect model; OR: 2.85, CI: 0.48, 17.05, random effects model), while high-risk AA were less likely to receive chemotherapy comparing to NHW (OR: 0.74, CI: 0.54-1.01, fixed effect model; OR: 0.73, CI: 0.54-0.99, random effects model). Intermediate-risk Asian and AA were more likely to receive chemotherapy compared to NHW (Asian to NHW; OR: 1.68, CI: 1.16-2.43, with fixed effect model, OR: 1.68, CI: 0.94-3.02, with random effects model; AA to NHW; OR: 1.16, CI: 0.93-1.46 with fixed effect model; OR: 1.06, CI: 0.62-1.79 with random effect model). Conclusions: We identified racial disparity in RS and post-RS treatment. Future research is required to elucidate the causes for AA and Asian receiving higher recurrence scores, a need for tailoring RS cutoffs for different races, and the utilization in adequate post-RS treatment.