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Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients
Ettore Capoluongo1, Gillian Ellison2, José Antonio López-Guerrero3
1Catholic University of the Sacred Heart and A. Gemelli Teaching Hospital Foundation, Rome, Italy.
Abstract:
The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.
Insights
BRCA1/2 testing is crucial for ovarian cancer patients, guiding treatment decisions with PARPi therapy. Challenges in testing tumor DNA require technical recommendations for accurate germline and somatic mutation detection.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- The 2015 approval of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) for ovarian cancer has shifted BRCA1/2 testing paradigms.
- Patients are now tested for BRCA1/2 mutations for treatment decisions, not just familial risk assessment.
- Tumor testing is increasingly considered to identify patients with somatic BRCA1/2 mutations who may benefit from PARPi therapy.
Purpose of the Study:
- To review the challenges associated with BRCA1/2 testing in tumor tissue.
- To provide technical recommendations for accurate detection of germline and somatic BRCA1/2 mutations.
- To discuss considerations for integrating ovarian tumor genetic analysis into patient care pathways.
Main Methods:
- Review of technical and analytical challenges in analyzing DNA from formalin-fixed, paraffin-embedded specimens.
- Discussion of strategies for BRCA1/2 testing in tumor tissue.
- Consideration of ethical requirements and patient pathway integration.
Main Results:
- Formalin-fixed, paraffin-embedded specimens present significant technical difficulties for DNA analysis.
- Specific recommendations are needed for reliable BRCA1/2 testing in tumor samples.
- Integrating genetic analysis into patient care requires careful planning and ethical consideration.
Conclusions:
- Accurate BRCA1/2 testing in ovarian cancer is essential for PARPi therapy selection.
- Addressing technical challenges in tumor DNA analysis is critical for clinical utility.
- A comprehensive approach including technical, clinical, and ethical factors is necessary for effective implementation.
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