-
1.
Neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 study for clinical and biomarker analysis.
Yoo, C, Lee, SS, Song, KB, Jeong, JH, Hyung, J, Park, DH, Song, TJ, Seo, DW, Lee, SK, Kim, MH, et al
British journal of cancer. 2020;(3):362-368
-
-
Free full text
-
Abstract
BACKGROUND Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.
-
2.
The clinical value and usage of inflammatory and nutritional markers in survival prediction for gastric cancer patients with neoadjuvant chemotherapy and D2 lymphadenectomy.
Li, Z, Li, S, Ying, X, Zhang, L, Shan, F, Jia, Y, Ji, J
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2020;(3):540-549
-
-
Free full text
-
Abstract
BACKGROUND The clinical values of inflammatory and nutritional markers remained unclear for gastric cancer with neoadjuvant chemotherapy (NACT). METHODS The inflammatory, nutritional markers and their changes were analyzed for locally advanced gastric cancer with NACT. The predictive value was evaluated by the Cox proportional hazards regressions under three hypothesized scenarios. The nomograms including independent prognostic factors were plotted for survival prediction. RESULTS A total of 225 patients were included in the study. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index, and hemoglobin (Hgb) were significantly reduced, and the body mass index was significantly increased after NACT (all P < 0.05). The pre-NACT NLR [hazard ratio (HR) = 1.176, P = 0.059] showed a trend to correlate with the overall survival (OS) when only pre-NACT markers available; The post-NACT Hgb (HR = 0.982, P = 0.015) was the independent prognostic factor when only post-NACT markers available; The post-NACT Hgb (HR = 0.984, P = 0.025) and the change value of LMR (HR = 1.183, P = 0.036) were the independent prognostic factors when both pre- and post-NACT markers available. The nomogram had a similar Harrell's C-statistic compared to ypTNM stage (0.719 vs. 0.706). CONCLUSION For locally advanced gastric cancer, the NACT could significantly decrease some inflammatory markers. The pre-NACT NLR, the post-NACT Hgb and the change value of LMR had some values in survival prediction combined with age, sex, tumor location and the clinical stages under different clinical scenarios. The elevated initial NLR, the preoperative anemia and the greater change value of LMR implied a poor prognosis.
-
3.
Characterization of Stromal Tumor-infiltrating Lymphocytes and Genomic Alterations in Metastatic Lobular Breast Cancer.
Richard, F, Majjaj, S, Venet, D, Rothé, F, Pingitore, J, Boeckx, B, Marchio, C, Clatot, F, Bertucci, F, Mariani, O, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(23):6254-6265
Abstract
PURPOSE Invasive lobular carcinoma (ILC) represents the second most common histologic breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level. EXPERIMENTAL DESIGN We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed by experienced pathologists. Targeted sequencing and low pass whole-genome sequencing were conducted to detect mutations and copy-number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC (n = 135) and IDC (n = 563) from MSK-IMPACT. RESULTS Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (AKT1, ARID1A, ESR1, ERBB2, or NF1) and CNAs (PTEN or NF1 deletion, CYP19A1 amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in CDH1, ERBB2, FOXA1, and TBX3 mutations, in CDH1 deletions and a decrease in TP53 mutations was observed in ILC as compared with IDC metastases. CONCLUSIONS ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.
-
4.
Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.
Chi, JT, Lin, PH, Tolstikov, V, Oyekunle, T, Chen, EY, Bussberg, V, Greenwood, B, Sarangarajan, R, Narain, NR, Kiebish, MA, et al
Cancer medicine. 2020;(11):3691-3702
Abstract
Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT-associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3-hydroxybutyric acid and ketogenesis. Third, many acyl-carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3-formyl indole (a.k.a. indole-3-carboxaldehyde), a microbiota-derived metabolite from the dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT-associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT-linked comorbidities and diabetes risk.
-
5.
Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.
Zamarin, D, Walderich, S, Holland, A, Zhou, Q, Iasonos, AE, Torrisi, JM, Merghoub, T, Chesebrough, LF, Mcdonnell, AS, Gallagher, JM, et al
Journal for immunotherapy of cancer. 2020;(1)
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. METHODS Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. RESULTS Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p<0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5-∞), with evidence of benefit from postimmunotherapy regimens. CONCLUSIONS Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.
-
6.
Identification of long-term survival-associated gene in breast cancer.
Ning, S, Li, H, Qiao, K, Wang, Q, Shen, M, Kang, Y, Yin, Y, Liu, J, Liu, L, Hou, S, et al
Aging. 2020;(20):20332-20349
Abstract
Breast cancer patients at the same stage may show different clinical prognoses or different therapeutic effects of systemic therapy. Differentially expressed genes of breast cancer were identified from GSE42568. Through survival, receiver operating characteristic (ROC) curve, random forest, GSVA and a Cox regression model analyses, genes were identified that could be associated with survival time in breast cancer. The molecular mechanism was identified by enrichment, GSEA, methylation and SNV analyses. Then, the expression of a key gene was verified by the TCGA dataset and RT-qPCR, Western blot, and immunohistochemistry. We identified 784 genes related to the 5-year overall survival time of breast cancer. Through ROC curve and random forest analysis, 10 prognostic genes were screened. These were integrated into a complex by GSVA, and high expression of the complex significantly promoted the recurrence-free survival of patients. In addition, key genes were related to immune and metabolic-related functions. Importantly, we identified methylation of MEX3A and TBC1D 9 and mutations events. Finally, the expression of UGCG was verified by the TCGA dataset and by experimental methods in our own samples. These results indicate that 10 genes may be potential biomarkers and therapeutic targets for long-term survival in breast cancer, especially UGCG.
-
7.
Investigation of Potential Genetic Biomarkers and Molecular Mechanism of Ulcerative Colitis Utilizing Bioinformatics Analysis.
Zhang, J, Wang, X, Xu, L, Zhang, Z, Wang, F, Tang, X
BioMed research international. 2020;:4921387
Abstract
OBJECTIVES To reveal the molecular mechanisms of ulcerative colitis (UC) and provide potential biomarkers for UC gene therapy. METHODS We downloaded the GSE87473 microarray dataset from the Gene Expression Omnibus (GEO) and identified the differentially expressed genes (DEGs) between UC samples and normal samples. Then, a module partition analysis was performed based on a weighted gene coexpression network analysis (WGCNA), followed by pathway and functional enrichment analyses. Furthermore, we investigated the hub genes. At last, data validation was performed to ensure the reliability of the hub genes. RESULTS Between the UC group and normal group, 988 DEGs were investigated. The DEGs were clustered into 5 modules using WGCNA. These DEGs were mainly enriched in functions such as the immune response, the inflammatory response, and chemotaxis, and they were mainly enriched in KEGG pathways such as the cytokine-cytokine receptor interaction, chemokine signaling pathway, and complement and coagulation cascades. The hub genes, including dual oxidase maturation factor 2 (DUOXA2), serum amyloid A (SAA) 1 and SAA2, TNFAIP3-interacting protein 3 (TNIP3), C-X-C motif chemokine (CXCL1), solute carrier family 6 member 14 (SLC6A14), and complement decay-accelerating factor (CD antigen CD55), were revealed as potential tissue biomarkers for UC diagnosis or treatment. CONCLUSIONS This study provides supportive evidence that DUOXA2, A-SAA, TNIP3, CXCL1, SLC6A14, and CD55 might be used as potential biomarkers for tissue biopsy of UC, especially SLC6A14 and DUOXA2, which may be new targets for UC gene therapy. Moreover, the DUOX2/DUOXA2 and CXCL1/CXCR2 pathways might play an important role in the progression of UC through the chemokine signaling pathway and inflammatory response.
-
8.
RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy.
Mini, E, Lapucci, A, Perrone, G, D'Aurizio, R, Napoli, C, Brugia, M, Landini, I, Tassi, R, Picariello, L, Simi, L, et al
International journal of cancer. 2019;(9):2580-2593
-
-
Free full text
-
Abstract
Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.
-
9.
Genetic Ancestry-dependent Differences in Breast Cancer-induced Field Defects in the Tumor-adjacent Normal Breast.
Nakshatri, H, Kumar, B, Burney, HN, Cox, ML, Jacobsen, M, Sandusky, GE, D'Souza-Schorey, C, Storniolo, AMV
Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;(9):2848-2859
Abstract
PURPOSE Genetic ancestry influences evolutionary pathways of cancers. However, whether ancestry influences cancer-induced field defects is unknown. The goal of this study was to utilize ancestry-mapped true normal breast tissues as controls to identify cancer-induced field defects in normal tissue adjacent to breast tumors (NATs) in women of African American (AA) and European (EA) ancestry. EXPERIMENTAL DESIGN A tissue microarray comprising breast tissues of ancestry-mapped 100 age-matched healthy women from the Komen Tissue Bank (KTB) at Indiana University (Indianapolis, IN) and tumor-NAT pairs from 100 women (300 samples total) was analyzed for the levels of ZEB1, an oncogenic transcription factor that is central to cell fate, mature luminal cell-enriched estrogen receptor alpha (ERα), GATA3, FOXA1, and for immune cell composition. RESULTS ZEB1+ cells, which were localized surrounding the ductal structures of the normal breast, were enriched in the KTB-normal of AA compared with KTB-normal of EA women. In contrast, in EA women, both NATs and tumors compared with KTB-normal contained higher levels of ZEB1+ cells. FOXA1 levels were lower in NATs compared with KTB-normal in AA but not in EA women. We also noted variations in the levels of GATA3, CD8+ T cells, PD1+ immune cells, and PDL1+ cell but not CD68+ macrophages in NATs of AA and EA women. ERα levels did not change in any of our analyses, pointing to the specificity of ancestry-dependent variations. CONCLUSIONS Genetic ancestry-mapped tissues from healthy individuals are required for proper assessment and development of cancer-induced field defects as early cancer detection markers. This finding is significant in light of recent discoveries of influence of genetic ancestry on both normal biology and tumor evolution.
-
10.
Quantifying the association between acute leukemia and serum zinc, copper, and selenium: a meta-analysis.
Kim, S, Freeland-Graves, JH, Babaei, M, Sachdev, PK, Beretvas, SN
Leukemia & lymphoma. 2019;(6):1548-1556
Abstract
Acute leukemia is a clonal malignant disorder that occurs when immature blast cells accumulate in bone marrow. Zinc (Zn) and copper (Cu) are related to normal lymphocyte maturation and immune function regulation. Selenium (Se) is protective against oxidative damage. The aim of this meta-analysis is to statistically synthesize results from studies that have investigated the levels of Zn, Cu, and Se in acute leukemia patients. The effect size, delta, was used to standardize the raw data. The robust variance estimation (RVE) method was performed to measure the pooled effect size and variance. Results suggest significant negative differences for levels of serum Zn (p < .05, delta = -1.21; 95% CI, -2.13--0.28) and Se (p < .05, delta = -1.84; 95% CI, -3.39--0.29) and significantly positive differences between serum Cu levels (p < .01, delta = 1.94; 95% CI, 1.02-2.87) in acute leukemia, as compared to the controls.