A5038684427- BRCA gene mutations in cancer
- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Gene expression and cancer classification
- Ovarian cancer diagnosis and treatment
- Genomic variations and chromosomal abnormalities
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Advanced Breast Cancer Therapies
- Molecular Biology Techniques and Applications
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Health Systems, Economic Evaluations, Quality of Life
- Statistical Methods in Clinical Trials
- Breast Cancer Treatment Studies
- Cancer Cells and Metastasis
- Multiple and Secondary Primary Cancers
- Intraperitoneal and Appendiceal Malignancies
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- RNA and protein synthesis mechanisms
The Netherlands Cancer Institute
2015-2024
Oncode Institute
2015-2024
Cambridge University Hospitals NHS Foundation Trust
2024
Addenbrooke's Hospital
2024
University Hospital Cologne
2023
Leiden University Medical Center
2013-2018
Royal College of Surgeons in Ireland
2018
University College Dublin
2018
University of Cambridge
2018
Dutch Cancer Society
2018
PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer
Abstract Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal (IDC), accounting for around 10% of all cancers. The molecular processes that drive development ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis large patient cohort present here an integrated portrait ILC. Mutations in CDH1 PI3K pathway frequent alterations identified two main subtypes ILCs:...
The elevated levels of somatic copy-number alterations (SCNAs) in a subset high-risk endometrial cancers are suggestive defects pathways governing genome integrity. We sought to assess the prevalence homologous recombination deficiency (HRD) and its association with histopathologic molecular characteristics.
Triple negative (TN) breast cancers make up some 15% of all cancers. Approximately 10–15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required homologous recombination‐mediated DNA repair and deficiency results in genomic instability. BRCA1‐mutated tumors have a specific pattern copy number aberrations that can be used to classify as BRCA1‐like or non‐BRCA1‐like. mutation, promoter methylation, status genome‐wide expression data was determined 112 TN cancer samples with long‐term...
Patients with BRCA1-like tumors correlate improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed distinguish between and non-BRCA1-like tumors. We hypothesized that these may also be more sensitive PARP inhibitors than standard treatments. diagnostic expression signature (BRCA1ness) using a centroid model 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness then tested in HER2-negative patients (n =...
Testing for homologous recombination deficiency is required the optimal treatment of high-grade epithelial ovarian cancer. The search accurate biomarkers ongoing.
Abstract The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence‐free (RFS) and overall survival (OS) in patients stage III ovarian cancer. Homologous recombination deficient (HRD) tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD respond best treatment HIPEC. We analyzed the effect HIPEC OVHIPEC trial, stratified by status BRCA m status....
The lack of markers to predict chemotherapy responses in patients poses a major handicap cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response mouse model breast associated BRCA1 deficiency. Array-based profiling did not identify single marker predicting response, despite an increase Abcb1 (P-glycoprotein) was sufficient explain resistance several poor responders. Intertumoral heterogeneity explained the inability predictive signature...
In previous studies, high expression of XIST and low 53BP1 were respectively associated with poor systemic therapy outcome in patients resistance BRCA1-deficient mouse tumor models, but have not been evaluated patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified enriched for defects BRCA1 benefit from high-dose (HD) alkylating chemotherapy compared a conventional standard regimen. We investigated whether...
Abstract Data from clinical trials (CTs) drive advancements in practice. Despite most CTs now incorporating extensive translational portfolios, the diverse modalities of and sample data they generate often remain disconnected underutilised. SYNERGIA is a resource designed to integrate multi-modal multiple comparable format, that will be appropriately accessible clinicians researchers. The aims are to:1) Develop comprehensive, repository integrates longitudinal CT (>5 years), with...
Breast cancers in carriers of inactivating mutations the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This is shared with that inactivate through other mechanisms. Because important repair double-strand breaks error-free homologous recombination, patients BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces breaks.We investigated single institution cohort high-risk received tandem HD chemotherapy schedule comprising ifosfamide,...
Abstract Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature (“BRCA1-like”) and are hypersensitive to double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human tumors might predict sensitivity DSB-inducing drugs; (ii) inhibition potentiates cisplatin efficacy Brca1-deficient murine mammary tumors. Experimental Design: expression was analyzed 497 using IHC or RNA sequencing. We classified 370 by profiles as...
Background Phase III trial data have shown a significant benefit by the addition of maintenance treatment with niraparib, irrespective BRCA or HRD status, in patients advanced high-grade ovarian cancers; and, combination olaparib and bevacizumab compared monotherapy positive patients. However, it is unclear whether PARP inhibitor sufficient, if needed. Primary Objectives This will investigate strategy carboplatin/paclitaxel/bevacizumab/niraparib superior to carboplatin/paclitaxel/niraparib...
Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed test that assigns CN profiles to be ‘BRCA1‐like’ or ‘non‐BRCA1‐like’, which refers resembling BRCA1‐mutated tumor without mutation, respectively. Approximately one third of the BRCA1‐like breast has hypermethylation promoter and an unknown reason for being BRCA1‐like. This classification is indicative patients' response high dose alkylating platinum containing chemotherapy regimens,...
Abstract Background The addition of adjuvant capecitabine to standard chemotherapy early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and meta-analyses. However, many did not benefit. We evaluated the BRCA1 -like DNA copy number signature, indicative homologous recombination deficiency, as predictive biomarker for benefit TNBC subgroup FinXX trial. Methods Early-stage were between capecitabine-containing (TX + CEX:...
Abstract Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status response to therapy, targeting homologous recombination deficiency (HRD). Therefore, investigated BRCA1- classification in ovarian cancer, aiming acquire with similar properties as those cancer. Experimental Design: We analyzed DNA profiles of germline BRCA2-mutant cancers control tumors observed that existing did not sufficiently...
Preclinical studies in breast cancer models showed that BRCA1 or BRCA2 deficient cell lines, when compared to BRCA proficient are extremely sensitive PARP1 inhibition. When combining the inhibitor olaparib with cisplatin a BRCA1-mutated mouse model, combination induced larger response than either of two compounds alone. Several clinical have investigated single agent therapy combinations both drugs, but no randomized evidence exists for superiority carboplatin-olaparib versus standard care...