Stromal cell signature associated with response to neoadjuvant chemotherapy in locally advanced breast cancer
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PROVIDER: PRJNA601889 | ENA |
REPOSITORIES: ENA
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Project description:Background. There is evidence that the stromal compartment may influence breast cancer responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy in locally advanced breast cancer, considering tumor down staging (to at least ypT1a/b,ypN0), as the best response. Patients and methods. Forty four patients diagnosed with locally advanced breast cancer (29 classified as estrogen receptor (ER) positive and 15, as ER negative) were included. Neoadjuvant chemotherapy consisted of doxorubicin/cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. Stromal cells were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression Microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (Significance analysis of microarrays). Gene set enrichment analysis was used to identify gene sets correlated with the phenotype downstaging. Results: After chemotherapy, nine patients presented disease downstaging to maximum ypT1a-b/ypN0. Using SAM test (FDR 17), 11 sequences were differentially expressed, all of which (except for H2AFJ) more expressed in responsive tumors. Gene list enrichment analysis revealed three genes involved in abnormal cytotoxic T cell physiology: TOX, LY75 and SH2D1A. Gene sets correlated with tumor downstaging (FDR < 0.01), were mainly involved in immune response or lymphocyte activation, both in ER positive and ER negative samples. Conclusion: In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.
2020-01-18 | GSE143846 | GEO
Project description:To elucidate candidate genes and pathways associated with poor response, we retrospectively analyzed gene expression profiles in serial biopsies from women with locally advanced breast cancer who failed to respond to anthracycline-based chemo followed by taxane in the I-SPY Of the 221 patients who completed neoadjuvant chemotherapy, 215 patients had surgery with 73% not achieving a pathologic complete response (pathCR). In these patients, cDNA microarray expression profiles from pretreatment biopsy (T1) were compared to those biopsy specimens obtained 24-72 hours after initiation of treatment (T2) or in tumors surgically removed after chemotherapy (TS). Paired expression data for T1vsT2 and T1vsTS were available for 29 and 39 patients with no pathCR, respectively. Paired differential expression analyses were performed via Significance Analysis of Microarrays (SAM) and differentially expressed genes were subjected to Ingenuity Pathway Analysis
2015-06-12 | E-GEOD-32603 | biostudies-arrayexpress
Project description:Purpose: Identified the expression profile of lncRNA associated to neoadjuvant chemotherapy response in 11 tumor of locally advanced breast cancer patients Methods: We implemented the transcriptomic analysis from 11 breast cancer samples by paired-end RNA-Seq, as a case-control study (responders vs nonresponders group). Differential expression analysis for lncRNA and mRNA were made to identify lncRNA as predictive biomarkers. Results: We identified the over-expressed lncRNA GATA3-AS1 in nonresponders group. Additionally, we identified the pathways were differentially expressed lncRNA and mRNA are associated in neoadjuvant chemotherapy response. Conclusion: we propose lncRNA GATA3-AS1 as a potential predictive biomarker for patients with LABC luminal B-like subtype that will not respond to neoadjuvant chemotherapy
2021-07-12 | GSE159448 | GEO
Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.
2024-02-26 | GSE205035 | GEO
Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.
2024-02-26 | GSE207521 | GEO
Project description:Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard protocol for treating patients with locally advanced non-metastatic colorectal cancer (CRC) is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU), but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic CRC patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-two patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially expressed proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially expressed proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic CRC. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.
2018-06-25 | PXD008440 | Pride
Project description:MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been previously reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome. The pre-treatment sera of 42 stage II–III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs.
2013-07-20 | E-GEOD-49035 | biostudies-arrayexpress
Project description:The goal of the study was to identify a gene expression signature capable of predicting a pathological complete response following neoadjuvant anthracycline-based chemotherapy of breast cancer. The samples were taken from the FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) of the EORTC 10994 trial. EORTC 10994 is a phase III clinical trial comparing FEC with ET (epirubicin, docetaxel) in patients with large operable, locally advanced or inflammatory breast cancer (www.eortc.be). Frozen biopsies were taken at randomisation. RNA was extracted from 100um thickness of 14G core needle biopsies. Adjacent sections were tested by H&E to confirm >20% tumour cell content. 200 ng total RNA per chip was amplified using the Affymetrix small sample protocol (IVT then Enzo). 102 tumours were tested on Affymetrix X3P chips. Single biopsies were tested per tumour. The CEL files were quantile normalised using rma. The clinical response measure was pathological complete response (pCR, disappearance of the tumour after chemotherapy with at most scattered invasive cells detected by histology). 102 tumors
2008-12-19 | E-GEOD-4779 | biostudies-arrayexpress
Project description:The study objective was to find new biomarkers of treatment response and adverse events in patients receiving neoadjuvant therapy for locally advanced rectal cancer. Patients received neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) and underwent treatment evaluation four weeks after CRT completion. Radical pelvic surgery was planned 2-4 weeks later. Patients were scored for treatment adverse events, according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, throughout the neoadjuvant treatment course, including at NACT and CRT completion. Treatment response was assessed by histologic ypTN staging and tumor regression grade (TRG) scoring, as well as progression-free survival (time from Inclusion date to Date of local relapse or Date of metastatic disease, whichever came first) recorded for five years after surgery.
2016-04-21 | GSE65622 | GEO
Project description:Purpose: Identified the expression profile of lncRNAs associated to neoadjuvant chemotherapy response in 47 luminal B tumors of locally advanced breast cancer patients Methods: We implemented the transcriptomic analysis from 47 luminal B breast cancer samples by paired-end RNA-Seq, as a case-control study (responders vs nonresponders group). Differential expression analysis for lncRNA and mRNA were made to identify lncRNA as predictive biomarkers. Results: We identified a signature of lncRNAs associated with nonresponders group. Additionally, we identified the pathways were differentially expressed lncRNA and mRNA are associated in neoadjuvant chemotherapy response. Additionally, we proposed the clinical application of lncRNA GATA3-AS1 as a predictive biomarker to neoadjuvant chemotherapy response in luminal B breast cancer patients detected by RNA-ISH. Conclusion: we propose the clinical utility of lncRNA GATA3-AS1 detected by RNA-ISH to identify luminal B breast cancer patients that will not respond to neoadjuvant chemotherapy.
2024-08-27 | GSE270967 | GEO