“The additional refinements in the 2019 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer on what constitutes a family history of prostate cancer will help practitioners know what to inquire about,” said James L. Mohler, MD, Associate Director for Translational Research, Chief of Inter-Institutional Academics, and Professor of Oncology, Roswell Park Comprehensive Cancer Center. “We are advising that a more thorough history be taken for family members found to have genomic abnormalities, especially for homologous repair deficiency [HRD] genes [Figure 1]. We have refined the definition of what constitutes a first-degree relative, advised more careful ascertainment of Ashkenazi Jewish ancestry, and refined the definition of hereditary risk.”
Germline variants known to be associated with increased incidence and/or aggressiveness of prostate cancer include MSH2, MSH6, and MLH1 (Lynch syndrome) and BRCA1, BRCA2, ATM, PALB2, and CHEK2 (homologous recombination genes). The new guidelines call for germline testing for all of these using next-generation sequencing (NGS). Additional genes should be tested depending on clinical context. Some of these may not be actionable but are of value in family counseling (eg, HOXB13).
Another important feature in the 2019 version of the NCCN Guidelines for Prostate Cancer is a distinction between intraductal and ductal carcinoma. Although both can occur within the same biopsy and there can be overlap, a higher incidence of germline mutations may be found in intraductal carcinoma, which has treatment implications.
“Four different studies have found an association between DNA repair genes and intraductal carcinoma,” Dr. Mohler said. “Ongoing studies are prospectively testing this potential association.”
The 2019 guidelines recommend germline testing for all patients with intraductal carcinoma and state that germline testing should be “considered” for ductal carcinoma based on clinical features (Figure 2). “We have included when to recommend germline testing according to risk category and family history for all risk groups. The frequency of germline mutations represents a rapidly evolving knowledge base,” he said. “Some studies show that even as you capture patients at more advanced stages of prostate cancer, the frequency remains relatively low but targeted therapy may be quite beneficial.”
NGS for a full gene panel costs approximately $3,500 per patient. Targeted sequencing of specific genes can be performed at a reduced cost, and the cost to the patient depends on insurance coverage and patient co-pays. “A danger of limiting sequencing to save costs is that genes that can be targeted to affect the course of disease may be missed,” Dr. Mohler said.
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