“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.
Disclosures: Dr. Mohler has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Antonarakis has disclosed that he serves as a consultant for Amgen Inc., Astellas Pharma US. Inc., AstraZeneca Pharmaceuticals LP, Clovis Oncology, Dendreon Corporation, ESSA, GlaxoSmithKline, Janssen Pharmaceutica, Medivation, Inc., Merck & Co., Inc., and sanofi-aventis U.S.; that he has received grant/research support from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Dendreon Corporation, Genentech, Inc., Janssen Pharmaceutica, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, sanofi-aventis U.S., and Tokai; and that he has received royalty income from Qiagen.
Aghazadeh MA, Frankel J, Belanger M, . National Comprehensive Cancer Network favorable intermediate-risk prostate cancer – is active surveillance appropriate? J Urol 2018;199:1196–1201.
Messing EM, Manola J, Yao J, . Immediate versus deferred androgen deprivation treatment in patients with node-positive cancer after radical prostatectomy and pelvic lymphadenopathy. Lancet Oncol 2006;7:472–479.
Dong Z, Wang H, Xu M, . Intermittent hormone therapy versus continuous hormone therapy for locally advanced prostate cancer: a meta-analysis. Aging Male 2015;18:233–237.
Hussain M, Tangen CM, Berry DL, . Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;268:1314–1325.
Boevé LM, Hulshof MC, Vis AN, . Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomized clinical trial: data from the HORRAD trial. Eur Urol 2019;75:410–418.
- Search Google Scholar
- Export Citation
)| false . , Boevé LM , Hulshof MC , Vis AN Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomized clinical trial: data from the HORRAD trial. Eur Urol 2019; 75: 410– 418.
Parker CC, James ND, Brawley CD, . Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomized controlled phase 3 trial. Lancet 2018;392:2353–2366.
Fizazi K, Shore N, Tarnmela T, . Darolutamide in non-metastatic, castration-resistant prostate cancer [published online February 21, 2019]. N Engl J Med, doi: 10.1056/NEJMoa1815671
Marshall CH, Fu W, Wang H, . Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis 2019;22:59–65.
- Search Google Scholar
- Export Citation
)| false . , Marshall CH , Fu W , Wang H Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis 2019; 22: 59– 65. 30171229 10.1038/s41391-018-0086-1
Schweizer MT, Antonarakis ES, Bismar TA, . Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. [published online April 18, 2019]. J Clin Oncol Precis Oncol, doi: 10.1200/PO.18.00327
Abida W, Cheng ML, Armenia J, . Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade [published online December 27, 2018]. JAMA Oncol, doi: 10.1001/jamaoncol.2018.5801
Antonarakis ES, Shaukat F, Isaacsson Velho P, . Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Oncol 2019;75:378–382.