bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of NR2F1, a tumor dormancy marker, with cancer cell proliferation and lymph node metastasis, and expression in cancer-associated fibroblasts in breast cancer.
Authors: Wu Rongrong , Oshi Masanori , Asaoka Mariko , Tokumaru Yoshihisa , Ishikawa Takashi , Takabe Kazuaki 
Published: June 2022

e12550 Background: It is now well accepted that some cancer cells remain in quiescent state and survive through adjuvant systemic treatments, also known as tumor dormancy, which preserve the potential for late recurrence. NR2F1 is a known biomarker for dormant cancer cells, which suppress cell proliferation in experimental models. Here, we hypothesized that patient breast cancer (BC) with high NR2F1 gene expression is associated with less cell proliferation and worse survival. Methods: More than 7000 patients from 3 large-scale primary and 5 metastatic BC patient cohorts and 2 single-cell sequencing cohorts were analyzed. Results: NR2F1 expression was upregulated in dormant cell lines and in bone metastatic clone cells compared with mother 4T1 cells. High NR2F1 BC enriched multiple metastasis-related pathways such as TGFβ, EMT, angiogenesis, as well as cancer stem cell-related signaling (NOTCH, HEDGEHOG, and Wntβ-catenin). As expected, all 5 cell proliferation-related gene sets including E2F Targets and G2M Checkpoints were enriched in low NR2F1 BC, and so was MKI67 expression. Unexpectedly, there were no consistent association between NR2F1 expression and survival among the 3 cohorts. Three out of four cohorts demonstrated significantly high NR2F1 expression in primary BC with lymph node metastasis. There was no difference in NR2F1 expression in primary BC by the distant metastasis in the four cohorts, by the metastatic sites, or between the primary and metastatic BC neither. Given the discrepancy between the biology and clinical outcome of high NR2F1 BC, we performed the functional analysis exclusively . Surprisingly, there were no consistent enrichment of metastasis-related gene sets nor downregulation of cell proliferation-related gene sets to high NR2F1 expression cancer cells, unlike the analyses of bulk tumors. Intratumoral heterogeneity, HRD, proliferation score, and mutation load were all less in high NR2F1 BC, along with IFN-γ response and TIL fractions. Infiltration of immune cells such as Th1 and Th2 T-cells, M1 and M2 macrophages were all less, while stromal cells such as adipocytes, fibroblasts, stromal cells and endothelial cells were more abundant in high NR2F1 BC. Surprisingly, NR2F1 was barely expressed in cancer cells and was most highly expressed in cancer-associated fibroblasts consistently regardless of subtypes in two independent single-cell sequence cohorts. The expression of NR2F1 was higher in inflammatory than myofibroblastic CAFs, and that of CAFs, but not cancer cells, was associated with lymph node metastasis or advanced stage. Conclusions: The tumor dormancy marker NR2F1 expression in primary BC is associated with mechanism of metastasis and suppression of cancer growth, but is most expressed in cancer-associated fibroblasts in the tumor microenvironment.
De-escalation of chemotherapy in elderly women using a 70-gene platform: Comparison of the MINDACT study with a real-world study in the Brazilian population (AGEMA-BRA).
Authors: Mansani Fabio , Celinski Vitória , Freitas-Junior Ruffo 
Published: June 2022

e12568 Background: The application of genetic signatures can contributes to determine a less toxic treatment in ederly women with luminal biological profile tumors, where toxicity is less tolerated and with a higher risk of fatal outcomes by therapy. The MINDACT study evaluated this population using MammaPrint, but patients over 70 years of age were poorly represented, corresponding only to 0.8% of the patients evaluated (56 of 6693 patients), and only 26 patients with high clinical risk. Objective: The aim of this study was to verify the possibility of de-escalation of systemic treatment with the use of MammaPrint genetic signature in elderly women, comparing the prevalence of data from the MINDACT study population with a cohort of Brazilian patients submitted to the examination (AGEMA-BRA). Methods: Cross-sectional study comparing the prevalence of low and high risk genomic patients in a population with luminal profile breast carcinoma with high clinical risk in MINDACT study populations with a Brazilian cohort older than 70 years, evaluated by the genetic signature MammaPrint, between 2016 and 2020. Descriptive analysis of data with estimation of simple and relative frequencies of variables in relation to low and high risk classification and study populations (AGEMA-BRA and MINDACT). Then, the chi-square test was used to verify the differences between the proportions. To measure the intensity of differences/associations, relative risks (RR) and their 95% confidence intervals (95% CI) were calculated. The tests were considered significant when p <0.05. Results: From a database of 950 patients submitted to MammaPrint analysis from 2016 to 2020. The population older than 70 yo (71-84 yo) at the time of diagnosis was represented by 89 patients (9.4%), all with high clinical risk. Of these patients, 54 (60.7%) corresponded to low genomic risk and 35 (39.3%) at high genomic risk. The comparative analysis between the prevalence of the Brazilian population and the MINDACT study, in which the low genomic risk was 61.5% and the high genomic risk 38.5%, showed no statistical significance (RR 0.98 (0.69-1.39) p= 0.936). Conclusions: The comparative analysis of the prevalence among the results of MammaPrint in the MINDACT study and in a cohort of Brazilian women (AGEMA-BRA) in the population older than 70 years, showed no statistical difference. With the confirmation of MINDACT data in this age group in a three-fold larger cohort (AGEMA-BRA), it is inferable that, although the low representativeness in the studies, the genetic signature MammaPrint can be applied in the elderly woman. Evaluation of outcomes regarding relapse-free survival and overall survival, an ongoing study, is necessary to confirm the data obtained.
Axillary pathologic response after neoadjuvant chemotherapy and surgery according to breast cancers subtypes and survival impact.
Authors: Michel Eloise , Vincent Laura , Beltjens Françoise , Arnould Laurent , Ladoire Sylvain , Coutant Charles , Jankowski Clémentine 
Published: June 2022

e12595 Background: The rate of pathologic complete response in the axilla (pCRAx) according to breast cancer biologic subtypes and the impact of nodal response on survival are lacking. Methods: Inclusion criteria were all T-stage breast cancers with initial lymph node involvement (determined by clinical palpation and radiological assessment by ultrasound and/or 18F-FDG PET scan), non-metastatic, treated with neoadjuvant chemotherapy followed by surgery with axillary lymph node dissection, managed at the George-François Leclerc Cancer Center in Dijon, France, between 2000 and 2018. pCRAx was defined as the absence of invasive cells in the axillary lymph nodes ( i.e. ypN0). The Sataloff classification was used as reference on each pathological report. Patients with a Sataloff NA classification ( i.e. evidence of therapeutic effect, and no residual disease) were classified as having pCRAx. Univariate and multivariate analysis were performed to identify factors predictive of pCRAx. Then, we analysed recurrence-free survival (RFS) and overall survival (OS) according to the type of nodal response of the different tumor subtypes. Survival curves were constructed using the Kaplan Meier method and compared using the log rank test. Results: Among 437 patients included, 227 (52%) were pathologically proven node-positive disease by biopsy. pCRAx rate was 35% (n=153) but varied according to tumor subtypes: 69.4% in HR(Hormone Receptor)-/HER2-positive, 47.4% in HR-/HER2-negative, 46.7% in HR+/HER2-positive, 8.5% in HR+/HER2-negative. By multivariate analysis, the factors significantly associated with pCRAx were HER2-positive profile (OR 4.48 (2.14-9.65), p<0.001 if HR+; OR 8.02 (3.54-18.74), p<0.001 if HR-), triple negative tumors (OR 3.01; 95%CI [1.40-6.58], p=0.005), Scarff-Bloom-Richardson III grade (OR 7.05; 95%CI [2.35-30.41], p=0.002) and breast complete response (OR 18.69; 95%CI [9.67-38.53], p<0.001). Ten-year recurrence rates were 19.6% in ypN0, 30.4% in ypN1, 49.5% in ypN2, 61.5% in ypN3 patients ( p<0.001). pCRAx has a prognostic impact on RFS regardless of the tumor subtype. Ten-year overall survival rates were 87.6% in ypN0, 79.5% in ypN1, 58.8% in ypN2, 42.3% in ypN3 patients ( p<0.001). In subgroup analysis, pCRAx had an impact on OS for all tumor subtypes except HR+/HER2-positive tumors. Conclusions: Breast cancer is a heterogeneous disease in which pCRAx rates vary according to breast cancer subtypes. The impact of nodal response on survival was significant. With pCRAx rates ranging from 46% to almost 70% for the HR-/HER2-negative and HER2-positive tumors, pCRAx appears to be a good surrogate marker of long-term outcome in patients treated for these cancers.
Pyrotinib combined with EC-TH neoadjuvant therapy for patients with HER2-positive breast cancer: A multicenter, randomized, phase II, open-label trial.
Authors: Zhang Xiangmei , Zhang Shuo , Li Zhong , Niu Fengling , Cai Haifeng , Li Xianqiao , Han Meng , Huang Ruixue , Liu Yunjiang 
Published: June 2022

e12604 Background: Neoadjuvant therapy plays an important role in improving the clinical efficacy for patients with stage II-III epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), combined with capecitabine have demonstrated a promising anti-tumour activity in metastatic breast cancer. Here, we conducted a multicenter, randomized, phase II, open-label trial aiming exploring the outcomes of adding pyrotinib to EC-TH neoadjuvant therapy. Methods: Patients aged 18–65 years old with invasive carcinoma, cT1-4N0-3M0 stage, HER2-positive breast cancer were enrolled. Cases were randomly assigned into neoadjuvant therapy with four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (or Paclitaxel for Injection, albumin bound) and trastuzumab (EC-TH), or pyrotinib (400mg day 1-21) combined with EC-TH. Results: 56 patients had completed 8 cycles of neoadjuvant therapy (40 in the treatment group and 16 in the controlled group). 20 patients underwent radical surgery after neoadjuvant therapy. Compared with EC-TH along (37.5%, 3/8), the addition of pyrotinib to EC-TH neoadjuvant chemotherapy (py+EC-TH) significantly increased the pathological complete response (pCR)rate (75%, 9/12) in patients with HER2-positive breast cancer. The objective response rate (ORR) was 87.5% (7/8) vs 100% (12/12) . The most common adverse effects (AEs) in the treatment group was diarrhoea with grade 3 occurred in 3 cases (7.5% 3/40), which most limited in the first treatment cycle. No grade 3 diarrhoea was observed in controlled group. Other AEs including leukopenia occurred similarly in both groups and no cardiovascular dysfunction was observed. Conclusions: Pyrotinib added to EC-TH neoadjuvant therapy significantly increased the pCR rate, suggesting an applicable strategy for HER2-positive breast cancer. Clinical trial information: NCT04290793.
Tumor-infiltrating lymphocytes (TILs) dynamics in breast cancer patients receiving neoadjuvant therapy: A systematic review and meta-analysis.
Authors: Zerdes Ioannis , Zhu Yajing , Tzoras Evangelos , Matikas Alexios , Bergh Jonas C. S. , Valachis Antonios , Foukakis Theodoros 
Published: June 2022

e12620 Background: Increased baseline tumor-infiltrating lymphocytes (TILs) are associated with improved pathological complete response rates and better prognosis in HER2+ and triple negative breast cancer (TNBC) patients receiving neoadjuvant therapy (NAT). However, the role of TILs dynamics/change (ΔTILs) at the neoadjuvant setting remains unclear, thus a meta-analysis of the published studies was carried out. Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched for studies reporting on TILs expression in paired invasive breast cancer patient tissue samples before and after NAT. Data were extracted by two investigators (Y.Z., E.T.) and discordances were resolved by a third (I.Z.). Outcomes included pooled TILs rates pre- & post-treatment (also per subtype), pooled rates of ΔTILs and direction of change after NAT as well as correlation of ΔTILs with survival outcomes. Heterogeneity was assessed using the I2 statistic. Results: Of 1569 identified entries, 22 studies fulfilled the criteria and provided adequate data for the outcomes of interest. Overall, a significantly decreased level of TILs was observed after NAT in paired samples (pooled OR = 1.60, 95% CI: 1.12-2.30, p = 0.01; TILs as categorical variable). Regarding pooled rates of ΔTILs, a change was observed after NAT, irrespective of BC subtype. Among the different subtypes, the effect of NAT on TILs was most prominent in HER2+ disease with a direction towards decreased TILs to be more common (pooled ΔTILs rates: 14.4% increased vs 46.2%, decreased). In TNBC, bi-directional TIL kinetics were noted (pooled ΔTILs rates: 41.6% increased vs 37.1% decreased). An increase in ΔTILs in TNBC was associated with better disease-free/relapse-free survival in univariate analysis (HR = 0.59, 95% CI: 0.37–0.95, p = 0.03). Substantial between-study heterogeneity was observed in most analyses. Conclusions: The first to our knowledge meta-analysis on TILs dynamics during NAT in BC informs about differences in matched pre- and post-treatment patient samples and the prognostic implications of ΔTILs in TNBC. The potential clinical utility of the longitudinal assessment of immune response during neoadjuvant therapy warrants further investigation in prospective trials.
Safety, efficacy, and clinical outcomes of the anti-CCR5 inhibitor (Leronlimab): A pooled analysis of three clinical trials in patients with mTNBC.
Authors: Adams Daniel L , Raghavakaimal Ashvathi , Tang Cha-Mei , Gardner Kirby P , Kelly Scott , Pourhassan Nader , Ray Nitya 
Published: June 2022

e13062 Background: Metastatic triple negative breast cancer (mTNBC) is a highly invasive BC subtype with limited treatment options and poor clinical outcomes. Leronlimab, a humanized IgG4κ antibody, competitively inhibits CCR5, a cancer motility receptor and target for cancer inhibition. We report on a pooled analysis of n = 28 mTNBC patients (pts) showing that leronlimab has potent antitumor activity with improved 1 year progression free (PFS) & overall survival (OS) with few treatment emergent adverse events (TEAEs). Further, we explored the effect of leronlimab on circulating tumor associated cells (TACs) from peripheral blood as a surrogate and early predictor of drug response. Methods: mTNBC pts results from 3 blinded prospective clinical drug studies, Phase 1b/2 dose escalation (NCT03838367), Compassionate Use (NCT04313075), and Basket Study (NCT04504942) were pooled to evaluate leronlimab’s safety & efficacy at 12 months (mos). Pts received ≥1 dose of leronlimab alone (n = 2), with carboplatin (n = 11) or with physician’s choice (n = 15). Pts received 1-33 doses, ranging from 350mg (n = 9), 525mg (n = 16) or 700mg (n = 3). In addition, anonymized pt peripheral blood was procured before and after (̃30 days) induction as an exploratory biomarker, to evaluate TACs in predicting efficacy. Progressive disease, stable disease or partial response was determined by RESICT v1.1, and univariate analysis was used evaluate PFS & OS. Results: mTNBC pts were pooled from Phase 1b/2 (n = 10), Compassionate Use (n = 16), and Basket Study (n = 2) treated with 350-700mg doses, 4 pts escalating 350 to 525mg. Pts had 1-5+ prior systemic therapies for mTNBC (median = 2), median age 52 (range 33-84), ECOG 0 (n = 18) or ECOG 1 (n = 10), n = 17 had visceral mets, and n = 6 had brain mets. A total of n = 68 TEAEs were reported, with n = 7 grade I/II & n = 1 grade III related to leronlimab. At 12 mos, pts had a mPFS = 3.8 mos (95%CI 2.3-6.2) and mOS = 6.6 mos (CI95% 4.9-12+). However, pts treated with 525-700 mg doses (n = 19) had a > 75% improved mPFS = 6.1 mos (95%CI 2.3-7.5) and mOS 12+ mos (95%CI 5.5-12+). Further, a drop in circulating TACs was identified in 75% (n = 21/28) pts and predicted for significantly better clinical outcomes, mPFS = 6.2 and mOS > 12 mos. Conclusions: These studies suggest that mTNBC pts dosed with leronlimab had high clinical benefit, i.e. longer PFS & OS with few TEAEs, and leronlimab resulted in a drop in circulating TACs in the majority of pts correlating with early therapy response. Clinical trial information: NCT03838367, NCT04313075, NCT04504942.
Selective removal of soluble tumor necrosis factor receptors by apheresis as a novel immunotherapy approach for triple-negative breast cancer.
Authors: Ostrowski Adam , Segal Robert , Florin Lawrence , Anderson Nina , Manax Victoria G. , Marleau Annette , Josephs Steven , Wysocki Piotr Jan , Konopka Kamil Wladyslaw , Kwinta Lukasz , Potocki Pawel Michal 
Published: June 2022

e13065 Background: Although the activity of the cytokine TNF-α against diverse tumor types has been widely documented, safe and effective therapies for augmenting this pathway are lacking. An immunoadsorption device, the LW-02 Column, has been developed as a subtractive immunotherapy approach to remove soluble TNF-α receptors (sTNF-R1 and sTNF-R2) from cancer patients’ plasma using apheresis. Since soluble TNF-α receptors bind to and neutralize the activity of TNF-α, their depletion from plasma is performed to unleash the anti-tumor effects of endogenous TNF-α. The LW-02 Column contains an inert matrix to which a recombinant TNF-α polypeptide (single-chain TNF-α; scTNF) is covalently coupled as a ligand for capturing sTNF-R1 and sTNF-R2. This study evaluated key performance features of the LW-02 Column when used as a monotherapy or with chemotherapy in patients with advanced TNBC [ClinicalTrials.gov Identifier: NCT04004910]. Methods: As part of the ongoing clinical study, 28 patients with advanced TNBC underwent 862 LW-02 Column Immunopheresis procedures at 3 sites (mean=22.5; range=2–109) using the Spectra Optia Apheresis System (Terumo BCT, Inc.); 10 patients received LW-02 Column monotherapy and 18 received LW-02 Column therapy with various chemotherapy regimens. Therapy with the LW-02 Column was performed 3x/week for at least 16 weeks by processing 2 plasma volumes per treatment. Adverse events and tolerability of the therapy were monitored. Assessments were performed to determine the LW-02 Column’s target specificity and capture efficiency. The amount of scTNF ligand that could leach from the column during the procedures was also measured. Results: No serious device-related adverse events have been reported in this study. After 30 minutes of apheresis using the LW-02 Column, the mean capture efficiencies for sTNF-R1 and sTNF-R2 from TNBC patients’ plasma were 95.2% and 79.6%, respectively. The LW-02 Column was highly selective for removing sTNF-R1 and sTNR-R2 from total plasma proteins. The mean total amount of scTNF that may leach from the LW-02 Column (109 ng per apheresis session) is orders of magnitude lower than TNF-α concentrations that are known to trigger clinically meaningful effects. Conclusions: In patients with advanced TNBC, subtractive immunotherapy with the LW-02 Column either as a monotherapy or with chemotherapy is safe and achieves effective depletion of soluble TNF-α receptors from plasma. Evaluation of the safety and efficacy of the LW-02 Column is ongoing in TNBC patients as well as in studies of other solid tumor types. The LW-02 Column provides a novel and promising immunotherapy approach for augmenting the anti-cancer activity of the TNF-α pathway. Clinical trial information: NCT04004910.
Evaluation of an automated artificial intelligence (AI)/ natural language processing (NLP) engine to match patients (pts) with advanced solid cancers to biomarker-driven early phase (EP) clinical trials.
Authors: Morton Cienne , Ruta Daniel , Stavraka Chara , Anam Kaiser , Spicer James F. , Regan Aoife , Sengul Siru , Cernile George , Borecki Yulia , Schwering Taralyn , Rai Harpreet , Brierley Phil , Duroe Oenone , Quarterman Alan , Sarker Debashis 
Published: June 2022

e13513 Background: The increasing complexity of precision medicine in oncology creates significant challenges in identification of pts for biomarker-driven clinical trials. Worldwide expansion of genomic testing will identify more pts with potentially actionable alterations, but the manual task of matching pts to clinical trials requires laborious interpretation of fragmented medical information and knowledge of suitable trial eligibility criteria. Inspirata’s Trial Navigator (TN) solution uses AI and NLP to automatically extract relevant information from both patient medical records and trial protocols to identify appropriate trials. We conducted a retrospective study to evaluate the ability of TN to match pts referred to the Guy’s Hospital EP trials unit. Methods: Anonymised referral letters and genomic reports for pts referred from Jan 2019 to Dec 2020 were used. A subset was used to train TN to extract relevant variables for matching against eligibility criteria for all UK Experimental Cancer Medicine Centre (ECMC) Network trials open within 160 km of Guy’s Hospital at the time of referral, favouring biomarker-matched studies. Finally, TN was tasked with finding 5 ECMC trial matches for 40 referred pts. Matches were scored for eligibility and tumour and/ or biomarker suitability using a quality index (QI): 0, ineligible; 1, generic match; 2, tumour match; 3, biomarker match; 4, tumour and biomarker match. Results: Of 40 pts, most common tumour groups included gastrointestinal (55%), HNSCC (20%) and gynae (10%). TN was able to correctly identify at least 1 suitable trial (median = 4) for 39/40 pts (97%). Selection biomarkers were available for 27 pts, of whom 21 (78%) were matched to at least one appropriate biomarker-directed trial, 5 (12%) were matched to biomarker-agnostic trials and one was not correctly matched due to exclusion for progressive CNS metastases. Of 13 pts without biomarker information, 11 (84%) were matched to at least 1 tumour-appropriate trial and 2 to tumour-agnostic trials. Of all 200 trial matches, 134 (67%) were appropriately matched, of which 80 (59%) were external to Guy’s Cancer centre. Conclusions: TN successfully matched 90% of these preselected cancer pts to an appropriate biomarker- or tumour-directed trial, indicating potential to improve access and recruitment to early phase cancer trials, including those external to the primary treating site with which referrers may not be familiar. A prospective multicentre evaluation of TN is warranted to further define improvements in trial recruitment and efficiency.[Table: see text]