bluuebunny/crossref_metadata_2025 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]
Predicting patient response to cancer therapy via histopathology images.
Authors: Hoang Danh-Tai , Ben-Zvi Doreen , Hermida Leandro C. , Dinstag Gal , Elis Efrat , SInha Sanju , Sinha Neelam , Aharonov Ranit , Beker Tuvik , Stone Eric , Ruppin Eytan
Published: June 2022

e13561

Background: Histopathology has long been considered the gold standard of clinical diagnosis and prognosis in cancer. In recent years, molecular markers including tumor gene expression have proven increasingly valuable for enhancing diagnosis and precision oncology. Here we ask if we can predict tumor gene expression from its histopathology images and based on the latter, predict patient survival and treatment response. Methods: We developed DeepPT (Deep Pathology for Treatment), a deep learning framework that predicts gene expression directly from histopathology tumor images. DeepPT is composed of three main components: a pre-trained convolutional neural network model for feature extraction, an auto-encoder for feature compression, and a multiple-layer perceptron for regression. This architecture enables the model to capitalize on the similarity among the gene expressions and benefit from the advantages of multitask learning. Results: DeepPT was trained with haematoxylin and eosin stained (H&E) tumor slides from lung and breast cancer patients and their corresponding gene expression profiles. The models were then used to predict gene expression from five different held-out datasets, using nested cross validation. A total of approximately 23,000 genes were considered in this study; out of these, over 99% had a positive correlation between predicted and actual values, commonly for lung and breast cancer. Furthermore, a record number of genes (2,541 and 1,197 genes for lung and breast cancer, respectively) had a correlation above 0.4, well over the results of the current state-of-the-art approach (1,550 and 786 genes, respectively). We next studied if the inferred gene expression could be used for H&E-based personalized medicine. To this end, we used the predicted tumor transcriptomics generated by DeepPT as input to ENLIGHT, a platform that predicts a patient’s response to treatment from their tumor transcriptomics. We found that ENLIGHT matching scores based on DeepPT outputs were indeed associated with response to treatment. Conclusions: DeepPT is the first computational approach for building response predictors that can infer therapy response directly from whole slide images of patient biopsies. Importantly, its future application promises to make precision oncology more accessible to physicians and patients in the developing world.
Phenotypic and endotypic features of COPD associated with lung cancer development.
Authors: Lee Kyeryoung , Cohn David , Liu Zongzhi , Ai Lei , Paek Hunki , Jin Lan , Raja Kalpana , Li Minghao , Zhang Xingmin , Jun Tomi , Higashi Mitchell , Oh William , Calay Ediz S. , Savic Radoslav , Ghosh Krish , Kasarskis Andrew , Mullaney Tommy , Pan Qi , Schadt Eric , Wang Xiaoyan
Published: June 2022

e13563

Background: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with multiple phenotypes and endotypes and associated with lung cancer development. In this study, we analyzed the clinical features of COPD including various phenotypic and endotypic features from the electronic health records (EHR) as the potential risk factors for lung cancer development in a large cohort of COPD patients. Methods: We identified a COPD cohort based on electronic Medical Records and Genomics (eMERGE) network COPD cohort identification algorithms with minor modifications from the Mount Sinai Data Warehouse (2000-2020) and followed the patients on the first diagnosis of lung cancer. The development of lung cancer in COPD patients was confirmed by manual chart review. We retrieved the clinical features from EHRs and conducted Kaplan Meier (KM) analysis and multivariable Cox-regression modeling for hazard ratio (HR) analysis. Results: We found that 3.8 % of COPD patients (824 out of 21,658) developed lung cancer. While COPD patients with emphysema and smoking history (former or current) showed an increased risk of lung cancer onset, patients with concurrent asthma and corticosteroid (ICS) inhalation history showed a reduced risk of lung cancer onset (adjusted HR in Table). Interestingly, COPD patients with higher eosinophil counts showed late onset of lung cancer (>300 cells/ul, cancer rate at 5y=2.4%, p=< 0.002; 150-300 cells/ul, cancer rate at 5y=2.9%, p=0.003) when compared to patients with low eosinophils count (<150 cells/ul, cancer rate at 5y=3.4%) in a KM analysis. A multivariable analysis adjusted for age, gender, race, smoking status, COPD sub-phenotypes, severe exacerbation history, and ICS inhalation history showed a significantly lower risk of lung cancer in COPD patients with higher eosinophils count (150-300 cells/ul; HR: 0.82, 95% CI: 0.69-0.97, p=0.021 and >300 cells/ul; HR:0.72, 95% CI: 0.57-0.89, p=0.003) when compared to those with low eosinophils count (<150 cells/ul). Conclusions: Our study shows that many phenotypic and endotypic features of COPD are differentially associated with lung cancer development. High eosinophil levels, ICS usage, and concurrent asthma in COPD patients may reduce the risk of lung cancer development. [Table: see text]
Post-radiation cisplatin and etoposide as systemic treatment in newly diagnosed adult medulloblastomas: A retrospective, single institution, longitudinal evaluation of clinical outcomes and toxicity.
Authors: Komlodi-Pasztor Edina , Holdhoff Matthias , Ozer Byram Hirsch , Munjapara Vasu
Published: June 2022

e14046

Background: Medulloblastomas are malignancies of the posterior fossa with metastatic potential to the central nervous system. While a common pediatric malignancy, they are rare in adults. Extrapolating treatment regimens from pediatrics to adults is fraught as adults can developmentally tolerate higher radiation doses, but have less bone marrow reserve and therefore risk higher myelosuppressive toxicities with adjuvant systemic therapy. A standard systemic regimen for adults has not been delineated, though craniospinal radiation alone is likely insufficient in most cases. In the absence of well-established guidelines, our institution has historically used a combination of cisplatin (60 mg/m2 on Day 1) and etoposide (60-120 mg/m2 on Days 1-3 or 1-5) repeated in three-week cycles for three to a maximum of six cycles, but the literature to support this regimen is scant. Methods: In this retrospective chart evaluation, we reviewed the medical information of patients who were seen for newly diagnosed adult medulloblastoma between 1995 and 2020 at Johns Hopkins Hospitals. Those who met our pre-specified criteria (adjuvant treatment with etoposide/cisplatin within six months of craniospinal irradiation, sufficient data on toxicity before and after radiation, during chemotherapy, and one month after completion of the regimen, as well as sufficient clinical follow-up) were included in the analysis. Hematological toxicities were graded by NCI CTCAE guidelines. Follow-up for progression and survival were calculated from the end of the last chemotherapy administration and plotted on swimmers plots. Results: Ten out of 74 total adult medulloblastoma patients had adequate data about the tolerability of the regimen and clinical follow-up. Median time to follow-up was 46 months (range 4.5-164 months). Eight patients experienced Grade 3 and 4 hematological toxicities. Seven patients completed their planned treatment course, while two patients discontinued treatment prematurely because of hematological toxicities and one due to ototoxicity and fatigue. Three out of the ten patients progressed post-chemotherapy at 1 month, 24.5 months, and 44 months. Both early-progression patients died (7 and 29.5 months respectively), while the remaining eight are alive without evidence of progression. Conclusions: The data suggest a combination regimen of cisplatin and etoposide after craniospinal radiation in newly diagnosed adult medulloblastoma patients has acceptable toxicity and survival outcomes in this small patient cohort and compare favorably to other limited datasets in the literature. Further study is warranted to validate this as a recommended regimen.
Damage-associated molecular patterns (DAMPS) in patients with advanced cancer undergoing systemic treatment.
Authors: Valenti Vicente , Capdevila Laia , Ruiz Isabel , Badia Joan , Ramos Pascual Francisco Javier , Blázquez Susana , Villuendas Óscar , Pérez Cristina , Flores Gemma , Córdoba Mónica , Alonso Carlos
Published: June 2022

e14524

Background: Immunogenic cell death (ICD) is known for the release of DAMPS from tumor cells. We aimed to find signals of ICD by assessing the variation of plasma DAMPS (HMGB1 and S100A8) after vs. before standard of care (SoC) systemic treatment in patients with advanced solid tumors. Methods: Patients scheduled to start a new line of systemic treatment were included. Plasma concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. CD44 immunohistochemical (IHC) expression was determined in tumor tissue. After vs. before variation of paired median concentrations was analyzed with the Wilcoxon signed-rank test for the whole population and selected subgroups according to RECIST response, baseline plasmatic iron levels, CD44 expression, and platinum-based treatment. Results: Fifty-two patients were included. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment as first-line. Thirty-six patients (69%) received chemotherapy (CT) alone, ten (19%) CT plus targeted therapy (7 FOLFOX or XELOX plus bevacizumab, and one each FOLFOX plus cetuximab, FOLFOX plus panitumumab, docetaxel-trastuzumab-pertuzumab), two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Overall response rate (RECIST) was 42%, rate of patients with low baseline plasmatic iron levels was 53%, and CD44 expression was positive in 35% of the patients. Results on plasma concentration of DAMPS are shown in the table. Conclusions: Signals of ICD were not observed in these patients. HMGB1 variation was not significant while plasma concentration of S100A8 significantly decreased after treatment, more markedly in those patients who experienced tumor response.[Table: see text]
Combination of immune checkpoint inhibitors plus chemotherapy and risk of pneumonitis: A worldwide retrospective pharmacovigilance study.
Authors: Zheng Yi-Fan , Xu Pei-Hang , Li Zi-mu , Kuang Yu-Kun , Li Jia , He Jun-Hao , Chen Xiao , Tang Ke-Jing
Published: June 2022

e14587

Background: Pneumonitis is one of the most common fatal pulmonary adverse events that stem from immune checkpoint inhibitors (ICIs). Although the combination of ICI plus chemotherapy has become the standard first-line treatment regiments for various tumors, how the risk of pneumonitis changes during the combination treatments remains unclear. We used the World Health Organization pharmacovigilance database (VigiBase) to compare the risk of pneumonitis from the combinations of ICI plus chemotherapy with ICI in other regimens, including monotherapy. Methods: This observational, retrospective, pharmacovigilance study is a disproportionality analysis based on the individual case safety reports (ICSRs) extracted from the VigiBase from 1997 to 2020. The disproportionality analysis (known as case-non-case analysis) was conducted to compare the reporting of pneumonitis from the combination of ICI plus chemotherapy with ICI in other drug regimens, including monotherapy. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated. Results: From 1994 to 2020, A total of 93,623 ICI-associated ICSRs were reported in Vigibase, including 3,453 reports of pneumonitis (3.7%), among which 274 were associated with the combinations of ICI plus chemotherapy. The median time to event onset occurred about 2 months after therapy either in ICI without chemotherapy group or in the combination with chemotherapy group (61.5 days vs 74 days, respectively, p > 0.05). The ICI plus chemotherapy combination demonstrated a significant association with pneumonitis (ROR 1.35, 95% Cl 1.18-1.52). Among all the ICIs, anti-PD-1 antibodies combinations and anti-CTLA-4 antibodies combinations demonstrated a significant association with pneumonitis (PD-1+chemotherapy: 1.76, 95 % CI 1.52-2.05; CTLA-4+chemotherapy: 2.36, 95% Cl 1.67-3.35), while anti-PD-L1 antibodies plus chemotherapy combinations did not show similar association (ROR 0.37, 95% Cl 0.28-0.47). Conclusions: The combination of ICI plus chemotherapy is associated with higher risk of pneumonitis toxicity compared to other ICI-containing regimens (including ICI monotherapy) based on real-world data. The anti-PD-L1 plus chemotherapy combination has different pneumonitis profiles compared to anti-PD-1/CTLA-4 combinations. It suggests that a close monitoring for pneumonitis may be needed when using ICI plus chemotherapy combinations.[Table: see text]
A next generation site-specific ADC targeting breast and gastric cancer.
Authors: Italia James , Li Zhi , Hussain Myer , Boyce John , Warner Audrey
Published: June 2022

e15024

Background: Antibody drug conjugates are entering a renaissance period as a promising treatment option for a variety of cancers. Despite some success in the past few decades, developing effective ADCs remains a challenge due to extensive inefficiencies of industry standard conjugation technologies. Industry available methods can be limited by lack of site-specificity, inflexibility on the site of conjugation, and poor overall biophysical characteristics which can alter the efficacy, safety, and bioavailability of these therapeutics. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates which overcome these limitations and achieve the full potential of this highly promising class of therapeutics. Methods: In this work, we incorporate an azide-containing UAA (unnatural amino acid) into full-length antibodies targeting receptors overexpressed in breast and gastric cancer. Specifically, we have engineered variants of IgG1 antibodies to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as auristatins, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickADCs exhibit high therapeutic efficacy against receptor-positive cell lines, particularly lines expressing low levels of HER2, in vitro as well as in mouse xenograft models. Not only are the BrickADCs 100x more potent in demonstrated cell lines, but current research indicate that they have an improved safety profile over T-DM1 and extended half-life. Conclusions: It is conclusive that the BrickADC platform enables an increased therapeutic window. In other efforts, the BrickADC platform is leveraging a new Modular Multisite Platform to address the unmet need of eventual ADC resistance by conjugating multiple distinct payloads in a homogenous fashion. Continued preclinical work is underway for these pipeline candidates as well as investigation into other target areas.
Mechanisms of anticancer activity of bacteria in enhancing cancer immunotherapy.
Authors: Im Sin-Hyeog , Sharma Garima , Sharma Amit , Kim Inhae , Lee Soo-Woong , Lee Hye-Na , Park ChangWook , Rudra Dipayan
Published: June 2022

e15047

Background: Numerous studies indicate that selective microbiota could enhance anti-tumor immunity with checkpoint inhibitors. However, it is arduous to identify the best candidate bacteria strains and understand their underlying action mechanisms. Methods: We have developed Avatiome platform technology, an innovative pre-clinical model system that mimics the human body's immune system and microbiome. Avatiome incorporates up-to-date technologies such as immunophenotyping, single-cell transcriptomics, and an Artificial Intelligence system to develop novel therapeutics targeting neuronal, systemic inflammatory diseases, and cancers. Results: We have identified Lp IMB19 as an LBP candidate that can enhance anti-cancer immunity through this technology. Lp IMB19 suppresses tumor progression in pre-clinical models of melanoma, renal cancer, and NSCLC. Lp IMB19 efficiently potentiates the therapeutic effect of anti-PD-L1 in murine tumor models by enhancing the effector function of CD8+ T cells via altering the phenotypes of tumor-infiltrating macrophages with inflammatory M1 type. We have identified rhamnose-rich heteropolysaccharides (RHP) as key effector molecules to induce M1 macrophage in a TLR2 dependent manner. Lp IMB19 also limits the amount of iron availability via Lipocalin 2 (LCN2) to capture trace iron from the microenvironment and switch to an iron sequestration phenotype, subsequently inhibiting tumor growth. No side effect or toxicity is observed in pre-clinical toxicity studies. Conclusions: We are currently developing Lp IMB19 as an onco-biotics for clinical investigation as a live biotherapeutic product (LBP) combined with immune checkpoint inhibitors.
Hormonal indicator of effective mobilization of antitumor mechanisms in the experiment.
Authors: Zhukova Galina V. , Shikhlyarova Alla I. , Frantsiyants Elena M. , Kaplieva Irina V. , Engibaryan Marina A. , Volkova Viktoriya L. , Ulianova Yulia V. , Chernogorov Pavel V. , Ausheva Tatiana V. , Kit Oleg I.
Published: June 2022

e15054

Background: Previously, the antitumor efficacy of low intensity complex impacts, including electromagnetic radiation (EMR) of the extremely high frequency range (EHF) in combination with factors of electromagnetic or biochemical nature, was shown. The questions about systemic antitumor mechanisms and the role of the thyroid system in them are opened. The aim of the study was to evaluate changes in the levels of thyroid hormones and their ratio in the blood in the cases of tumor regression under the influence of complex impacts including EMR EHF. Methods: The experiments were carried out on outbred male rats of young (8-9 months) and senile (24-26 months) age with subcutaneously transplanted sarcoma 45 (S-45). EMR EHF (42.2 GHz, 10 mW/cm2) with previously developed regime of modulation was applied on the head. In young males (21), the tumor was additionally exposed to the electric field with neuron-like impulses (SCENAR-97.1 device); in 20 old animals, complexes of essential L-amino acids were used per os 260 mg/kg/day. The impact course lasted for 3 weeks. After its completion, the levels of thyroxine (T4) and triiodothyronine (T3) in the blood were assessed by radioimmunoassay and the T3/T4 ratio was calculated. The results were compared with the values in intact animals (n=9-10), control group rats (S-45, n=11-15) and animals of the main groups without tumor regression. The Kruskal-Wallis and Mann-Whitney criteria were used, and the coefficient of variation (cv) was determined. Results: The tumor growth was accompanied by a decrease in T3 by 1.7-2 times (p <0.05) without changes in T4. The studied impacts caused a complete regression of S-45 in 38% (8) of young males, as well as a regression by 75-100% in 25% (5) of old animals. Young rats with S-45 regression showed no decrease in T3, while in old animals the T3 decrease was 1.3 times less pronounced than in the control group (p <0.05). In young males without S-45 regression, a decrease in T3 at the tendency level was observed (p <0.1), and T3 in old rats did not differ from the control group. The level of T4 did not change. In all cases of S-45 regression, despite the variability of T3 and T4 separately (cv=31-68%), practically constant value of the T3/T4 ratio was noted (cv=2-4%). It was 16x10-5 in young animals and 13x10-5 in old ones. It differed by 12-94% from the T3/T4 in the comparison groups and in rats without tumor regression (p <0.05-0.01). In the latter cases, the T3/T4 ratio had significant variability (cv = 25-84%) and was outside the range of values in rats with tumor regression. Conclusions: The results indicate the participation of the thyroid gland in the effective mobilization of systemic antitumor mechanisms, the marker of which is the ratio of the thyroid hormone levels in the blood.
An alpha-fetoprotein-maytansine conjugate for the treatment of AFP receptor expressing tumors.
Authors: Sherman Igor A. , Boohaker Rebecca J , Stinson Karr , Griffin Patricia , Hill Wendy
Published: June 2022

e15056

Background: The alpha fetoprotein (AFP) receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and myeloid derived suppressor cells (MDSCs) but absent on normal tissues. By conjugating a novel maytansinoid toxin to a recombinant form of human AFP (ACT-101), we can selectively deliver the toxin to cancer and MDSC cells while sparing normal cells, thereby enabling a combination of targeted and immune activating approaches against the tumor. Methods: Four ACT-101-maytansinoid conjugates with different protein-toxin ratios and different linker chemistries were initially investigated in a mouse COLO-205 xenograft model, resulting in the selection of ACT-903 as the lead candidate for further development. A second study performed in the same tumor model compared the effects of single intravenous doses of ACT-903 (10-50 mg/kg) to control groups receiving either vehicle or the unconjugated protein, ACT-101 (25 mg/kg). Tumor growth, survival and clinical observations were assessed for 60 days post tumor implantation. Both serum ACT-101 and maytansinoid levels were measured following the single dose. Results: In the first study, a statistically significant reduction in tumor volume was seen for all four conjugates compared to vehicle control (p < 0.05). For ACT-903, tumors continued shrinking even after treatment completion, becoming undetectable in 9 of 10 animals. All 10 mice in this group survived through Day 60 with no obvious signs of toxicity. In contrast, there were no survivors in the control group. In the single dose study of ACT-903, a significant reduction of tumor burden compared to vehicle was achieved by Day 14 (p < 0.05) in both the 40 and 50 mg/kg dose groups. Mice in these 2 groups received a second dose 15 days after the first dose, based on observed tumor re-growth. Survival was significantly prolonged in the 50 mg/kg (p = 0.0037) and 40 mg/kg group (p < 0.0001) with 7 of 10 in the 50 mg/kg group and 9 of 10 animals in the 40 mg/kg group surviving to Day 60. Similar doses of ACT-101 and ACT-903 produced comparable ACT-101 serum levels, suggesting that the pharmacokinetic profile of the conjugate is driven primarily by the protein component. Free maytansinoid levels at 4 hours were less than 0.01% of the injected dose of the conjugate, indicating that the conjugate is stable in circulation. Conclusions: The efficacy and tolerability of ACT-903 in an animal tumor model supports advancing this conjugate toward clinical use with a regimen of either once a week or once every other week administration.
Comprehensive genomic profiling of MET rare tumors in China.
Authors: Li Ning , Wang Shuhang , Li Qin , Chen Rongrong , Fang Yuan , Ma Peiwen , Jiang Ning , Yu Yue , Miao Huilei
Published: June 2022

e15058

Background: The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, commonly activated by amplification, mutation and fusion. Methods: Rare tumor was defined as solid tumors with an incidence lower than 2.5/100,000 per year. We retrospectively analyzed the next-generation sequencing and clinicopathological data of 3453 Chinese rare tumors patients in the Geneplus database, including 1021 genes, MSI loci, tumor mutational burden (TMB), and programmed cell death ligand-1 (PD-L1) expression analysis information. Results: MET-positive was identified in 115 patients (3.3%), including 109 cases of amplification (3.2%), 8 cases of exon 14 skipping (0.2%) and 1 cases of fusion. The prevalence of MET-positive varied widely across tumors systems and subtypes. Urinary, neural, skin and respiratory systems were the top 4 systems with 8.3% (1/12), 7.9% (58/732), 4.2% (1/24) and 2.9% (6/207) MET-positive rate, respectively. Considering the tumor subtypes, glioblastoma, sarcomatoid carcinoma, neuroendocrine tumor and glioma were higher, reaching 15.7% (16/102), 13.2% (7/53), 9.8% (4/41), and 7.4% (36/487) respectively (Table). Totally, 73.0% of patients had at least one common targetable gene mutation, including ATM，BRAF，BRCA，CDKN2A，EGFR substitution, ERBB2, FGFR1,2,3, KIT, NF1, PIK3CA, PTEN and RET. The proportions of TMB-H (≥9 mut/Mb) and MSI-H were very low, with only 8.9% and 2.2%, while PD-L1 positive rate reached to 60.9%. Conclusions: The treatment options for rare tumors are still limited. The approval of MET receptor tyrosine kinase has brought hope to patients with Non-Small Cell Lung Cancer. The MET-positive rate in rare tumors is higher than 2.7% in lung adenocarcinoma, so MET receptor tyrosine kinase have great application potential in rare tumors. However, since most patients co-occurred with other targetable driver mutations or PD-L1 positive, how to choose the best treatment strategy should be solved. The deployment of the best treatment strategy is a problem that should be solved in the follow-up study.[Table: see text]