160P - CICLADES-CE study: Genomic signatures detected in DNA from FFPE samples of patients with advanced or metastatic breast cancers treated with anti-aromatase and CDK4/6 inhibitors

Background

Hormonal BCs are characterized by the expression of hormonal receptors (estrogen or progesterone). They can be treated with endocrine therapy (ET) including anti-aromatase inhibitors (AI) and/or anti-cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. However, such treatments can cause cancer cells to mutate and impact genes such as ESR1, PIK3CA and/or AKT1, which are associated with ET resistance. By establishing the baseline level of these mutations in Formalin-Fixed Paraffin-Embedded (FFPE) DNA from patients with advanced or metastatic BC treated with AI and CDK4/6 inhibitors, the CICLADES-CE study, ancillary to CICLADES trial aims to identify genomic signatures to be monitored during follow-up of clonal evolution.

Methods

Twenty FFPE samples from female patients diagnosed with advanced BCs and treated with AI were qualified, selected and microdissected. The AllPrep® DNA/RNA FFPE kit (Qiagen) was used to extract DNA. A method of Hybridization Capture-based Target Enrichment with a 516-gene panel was used on the NextSeq 550® (Illumina) for sequencing. Single nucleotide variants, copy number variants and telomere length were detected. Data obtained were then analyzed to identify highly mutated genes, specific mutations in genes of interest and genomic signatures as described by Alexandrov et al, 2013.

Results

Among 20 samples, 19 reached the quality criteria to be sequenced. We showed that several genes involved in the PI3-Kinase pathway were mutated across several samples, but no relevant mutations of AKT and ESR1 were found at baseline. Among the samples, 3 genomic signatures were detected, corresponding to validated COSMIC (Catalogue of Somatic Mutations in Cancer) signatures 5, 6 and 30. Those signatures are associated with DNA damage repair and deficiency of the base excision repair system.

Conclusions

The signatures found are a mirror of the samples origin and the type of fixation used. With this information we have created a focused gene panel to be used for ctDNA follow-up analysis. It also provides us with a clear baseline mutational landscape for the profiling of the rest of the CICLADES cohort.

Editorial acknowledgement

Clinical trial identification

CIrCuLAting Dna ESr1 Gene Mutations Analysis (CICLADES): NCT03318263 First posted: October 23, 2017.

Legal entity responsible for the study

Institut de Cancérologie de Lorraine, Service de Biopathologie, CNRS UMR 7039 CRAN Université de Lorraine.

Funding

Cancéropôle de l'Est and AstraZeneca.

Disclosure

V. Massard: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Eli Lilly, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Gilead Sciences, Astellas Pharma, Janssen Pharmaceuticals, Laboratoires Pierre Fabre; Financial Interests, Institutional, Funding: AstraZeneca. All other authors have declared no conflicts of interest.