Diagnostics and Patient Selection

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Patients with tumours that harbour BRCA mutations are more likely to respond to PARP inhibition, and identifying these patients is now well established in clinical practice. A BRCA mutation detected in a tumour can be germline or somatic in origin. A blood test to detect BRCA mutations in DNA isolated from whole blood samples is required to determine if the mutation is germline (blood test positive) or somatic (blood test negative). Somatic (sBRCA) mutation status is determined by tumour (tBRCA) sequencing and germline (gBRCA) mutation testing in blood.

Most indications require patient identification prior to treatment using BRCA testing for germline or somatic mutations. Accordingly, companion diagnostics have been developed to aid this process, and an up-to-date list of FDA approved companion diagnostics can be found at www.fda.gov.

Outside of the US, BRCA testing does not have to be done by specific companies, but can be performed by any certified laboratory.

Other biomarker tests are also being investigated to identify patients with genetic alterations beyond BRCA1/2 that are more likely to respond to PARP inhibitors and agents targeting DDR [1-10]. 

References

1. Abkevich V, Timms KM, Hennessy BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776-1782.
2. Cruz C, Castroviejo-Bermejo M, Gutierrez-Enriquez S et al. RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann Oncol 2018; 29: 1203-1210.
3. Davies H, Glodzik D, Morganella S et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017; 23: 517-525.
4. Graeser M, McCarthy A, Lord CJ et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res 2010; 16: 6159-6168.
5. O'Kane GM, Connor AA, Gallinger S. Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer. Trends Mol Med 2017; 23: 1121-1137.
6. Pennington KP, Walsh T, Harrell MI et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014; 20: 764-775.
7. Ramus SJ, Song H, Dicks E et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst 2015; 107.
8. Southey MC, Goldgar DE, Winqvist R et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 2016; 53: 800-811.
9. Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 2014; 16: 211.
10. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].