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Germline sequencing of advanced prostate cancer patients in the BARCODE2 trial

Date

30 Sep 2019

Session

Poster Display session 3

Presenters

Sarah Benafif

Citation

Annals of Oncology (2019) 30 (suppl_5): v325-v355. 10.1093/annonc/mdz248

Authors

S. Benafif1, R. Rageevakumar1, I. Whitmore2, C. Cieze-Borrella1, E. Saunders1, Z. Kote-Jarai1, R. Eeles2

Author affiliations

  • 1 Cancer Genetics, Institute of Cancer Research, SM2 5NG - Sutton/GB
  • 2 Cancer Genetics, Royal Marsden Hospital Institute of Cancer Research, SM2 5NG - Sutton/GB
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Background

The BARCODE2 trial is investigating the response to platinum chemotherapy in men with advanced prostate cancer (PrCa) and a germline mutation in a DNA repair gene. We present the germline DNA sequencing results for 94 men who underwent genetic screening.

Methods

Eligible men with advanced PrCa consented to trial entry and provided a blood sample for DNA extraction and sequencing. All patients were known to have metastatic castration resistant PrCa (mCRPC) and had been treated with one or both of: Docetaxel chemotherapy and an androgen receptor targeted agent. Next generation sequencing (NGS) using a customised 115 gene panel (Agilent Technologies) was carried out on a MiSeq machine. Protein truncating variants (PTVs) in DNA repair genes by NGS were validated by Sanger sequencing. Patients found to carry a PTV were eligible to receive carboplatin upon disease progression.

Results

94 patients have undergone genetic testing. The median age of patients entering the trial was 67 (range 46-84). 21 patients (22%) carried one or more PTVs in a DNA repair gene: 3 carriers of a BRCA2 variant and 3 carriers of a variant in ALKBH3, 2 carriers of an ATM variant and 2 carriers of a PALB2 variant. One of the ATM variant carries also carried a PTV in POLQ and 2 further carriers of the same POLQ variant were identified. One carrier was identified to carry a variant in each of the following genes: MRE11A, PARP2, BLM, CHEK2, EXO1, LIG4, FANCD2, MSH5 and PMS1. Of the 20 identified PTVs, 11 are classified as pathogenic or likely pathogenic in ClinVar. There was no significant difference in the age at PrCa diagnosis between carriers and non-carriers (mean age 59 years vs 60; p = 0.34). There was also no difference in the presence of a family history of cancer.

Conclusions

The initial NGS results in the BARCODE2 trial demonstrate a higher frequency of germline mutations in mCRPC patients compared with previously published data. This study is ongoing and aims to sequence 450 patients. If the frequency of germline mutations in men with advanced PrCa is confirmed to be 20% or higher, this would support the roll-out of routine genetic testing in the oncology setting to identify men who may benefit from targeted treatments such as platinum chemotherapy and PARP inhibitors.

Clinical trial identification

NCT02955082.

Editorial acknowledgement

Legal entity responsible for the study

Institute of Cancer Research.

Funding

European Research Council.

Disclosure

All authors have declared no conflicts of interest.

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