Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance
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ABSTRACT:
PROVIDER: PRJNA789839 | ENA |
REPOSITORIES: ENA
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Project description:When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identifiy biomarkers of response and resistance mechanims. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatmane sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.
2021-12-18 | GSE191127 | GEO
Project description:When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.
| EGAS00001005876 | EGA
Project description:When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.
| S-EPMC9076915 | biostudies-literature
Project description:Methylome-wide DNA methylation profiling of spatially separated breast tumor samples pre- and post-neoadjuvant chemotherapy (NAC) to characterize methylation heterogeneity alteration by NAC. The Illumina Infinium HumanMethylation450K Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 485,000 CpGs in the 47 samples derived from 8 breast cancer patients.
2019-01-31 | GSE106360 | GEO
Project description:Epigenome analysis of pre- and post-neoadjuvant chemotherapy breast tumor samples
| PRJNA416463 | ENA
Project description:The impact of platinum and taxol based neoadjuvant chemotherapy on tumour-associated macrophages (TAMs) was examined by analysis of TAMs extracted from high grade serous ovarian cancer (HGSOC) samples pre and post chemotherapy.
2021-04-20 | GSE158739 | GEO
Project description:In metastatic cancer, the degree of heterogeneity of the tumor-immune microenvironment and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy in high-grade serous ovarian cancer (HGSOC), we performed immunogenomics analysis of treatment-naive and paired pre/post-chemotherapy treated samples. In treatment-naive HGSOC, we find that immune cell-excluded and inflammatory microenvironments co-exist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of tumor microenvironment cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following neoadjuvant chemotherapy, increased natural killer cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors. The goal of this particular experiment was quantify RNA expression using microarray technology, and then evaluate differences in the trasncirptomic landscape of treatment naïve metastatic high grade serous ovarian cancer.
2020-03-14 | GSE146963 | GEO
Project description:Background: Over the past few years, immune checkpoint inhibitors have changed the therapeutic landscape of non-small-cell lung cancer (NSCLC). Response to immune checkpoint inhibitors correlates with a pre-existing anti-tumoral immune response. Checkpoint inhibitors have been introduced as second line therapy and are only very recently used as monotherapy or in combination with chemotherapy as first line treatment of NSCLC. However, the effect of conventional first line platinum-based chemotherapy on the immune infiltrate in the tumor is largely unknown. Methods: We measured the gene expression of a custom set of 201 cancer- and immune-related genes in 100 NSCLC tumor biopsies collected before chemotherapy and 33 re-biopsies after platinum-based chemotherapy at the time point of progression. For 29 patients matched pre- and post-chemotherapy samples could be evaluated. Results: We identified a cluster of 47 co-expressed immune genes, including PDCD1 (PD1) and CD274 (PD-L1), along with three other co-expression clusters. Chemotherapy decreased the average gene expression of the immune cluster while no effect was observed on the other three cluster. Within this immune cluster, CTLA4, LAG3, TNFRSF18, CD80 and FOXP3 were found to be significantly decreased in patient-matched samples after chemotherapy. Conclusion: Our results suggest that conventional platinum-based chemotherapy negatively impacts the immune microenvironment at the time point of secondary progression.
2020-07-14 | GSE154286 | GEO
Project description:Long noncoding RNA expression profile of breast cancer tissues pre- and post-neoadjuvant chemotherapy
| PRJNA912689 | ENA
Project description:Oesophageal cancer is the ninth most common cancer in the UK and accounts for 5% of all cancer deaths. The incidence of the disease in men has risen 50% in the last 25 years with the commonest pathological subtype in the West being adenocarcinoma, while in East Asia oesophageal squamous cell carcinoma predominates. Despite efforts to screen for Barrett’s oesophagus, and pre-operatively select OAC patients who are likely to benefit from potentially curative surgery, survival remains poor. The five year survival rate is less than 17% and even in early stage locoregional confined disease this figure lies between 25-35%. A significant improvement in overall survival has been demonstrated with neo-adjuvant or peri-operative chemotherapy but the optimal approach for individual patients remains unclear. A consistent finding has been that complete histopathological response to neo-adjuvant chemotherapy is a prognostic biomarker for increased survival benefit. Therefore, there is a pressing need to identify biomarkers capable of predicting response, enabling clinicians to select patients for whom neo-adjuvant therapies would be beneficial. This experiment represents gene expression profiling of 60 pre-treatment formalin-fixed paraffin embedded (FFPE) oesophageal adenocarcinoma biopsies. All patients were treated with neo-adjuvant cisplatin-based chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre from 2004-2012. The aim of the experiment was to carry out functional enrichment of pathological responders and non-responders to neo-adjuvant chemotherapy in order to identify novel mechanism of drug resistance or chemo-sensitivity.
2018-05-10 | E-MTAB-4666 | biostudies-arrayexpress