DNA damaging agents such as anthracyclines and alkylating agents are commonly used in neoadjuvant treatment of breast cancer. Around 20 – 40% of patients will have a complete clinical response, and a smaller proportion a pathological complete response (pCR), to these treatments. However, many patients will not respond to DNA damaging chemotherapy and therefore gain no benefit from treatment. At present there is no reliable method to predict likely reponse to DNA damaging agents.
The Fanconi anaemia (FA)/BRCA pathway is key for co-ordination of DNA repair after DNA damaging chemotherapy, and loss of this pathway is likely to predict for sensitivity to DNA damaging agents. Using DNA microarray data from 21 FA patients and 107 breast tumours (enriched for BRCA1/2 mutants), genetic processes associated with a DNA damage repair deficiency were identified. A microarray based 44 gene assay that could be used to prospectively identify these patients from formalin-fixed paraffin-embedded (FFPE) tissues was developed. This assay has been demonstrated to predict pCR after neoadjuvant DNA-damaging chemotherapy, and also 5 year relapse free survival after adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC)1.
The Neo-DDRD study was designed to assess the feasibility of using this assay for the selection of neoadjuvant chemotherapy, and to inform the practicality of using this assay for stratification in a prospective phase II clinical trial. This pilot study is a single-centre, non-randomised feasibility study of 30 women with a histologically confirmed diagnosis of breast cancer, where neoadjuvant chemotherapy is the primary treatment modality of choice.
- To assess the feasibility of carrying out the DDRD assay on diagnostic, FFPE core biopsy specimens
- To establish the minimum tumour content required within core biopsy specimens to successfully carry out the assay
- To evaluate the turn-around time for the assay to assess the feasibility of integration into the breast cancer treatment pathway
- To assess the correlation of DDRD assay scores and pathological tumour response
- Exploratory biomarker analysis on serial tissue and plasma specimens
- age > 18 years
- early (T1-3, N0-1), locally advanced or inflammatory breast cancer
- absence of metastatic disease on routine staging
- normal left ventricular function, haematological and biochemical parameters
- ECOG PS 0-1
- Metastatic disease
- Bilateral breast cancer
- Pregnancy/breast feeding
- Inability to give informed consent