ASCO 2017: Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer
The authors of this study evaluate their targeted gene panel in men with PCa and evaluate clinical factors in relationship to current guidelines for genetic screening. They completed DNA sequencing and exon-level copy number analysis on 1158 men with PCa between 2013 and 2016 at a commercial diagnostic laboratory. The genes requisitioned consistently included 14 genes on a hereditary PCa panel, most of which were DNA repair genes (full list: ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, TP53, PALB2, RAD51D). Blood and saliva samples were utilized for assessment. In terms of clinical data, they assessed Gleason scores and eligibility for genetic screening based on any NCCN testing criteria in patients with positive findings (pathogenic, likely pathogenic, and risk allele).
To clarify, the current NCCN guidelines1 states that a male warrants genetic counseling and to consider genetic testing if he has prostate cancer of Gleason score 7 or higher and one of the following:1 at least one close blood relative with ovarian cancer or breast cancer at age 50 or younger, or (2) at least two relatives with breast, ovarian, or prostate cancers (Gleason 7 or higher) at any age. The NCCN states that unaffected men may also consider genetic evaluation if their family history meets the same criteria, although testing of an affected relative is preferred, if possible.
When the 1158 men were assessed, pathogenic findings were identified in 199 (17.2%) patients, and 12 pts (1.0%) had two variants. 65.5% of variants occurred in genes other than BRCA1/BRCA2, including 9.5% in MMR genes associated with Lynch syndrome. Therefore, 34.5% were BRCA1/BRCA2 mutations.
Further findings:
- Positive variants in HOXB13, a gene associated only with PCa risk, were identified in eight (3.8%) pts.
- Positive variants in CHEK2 were identified in 14.6% of pts, second only to BRCA2
- DNA mismatch repair variants, alterations with substantial known therapeutic implications, were detected in 1.7% of samples.
- 12.4% of pts with Gleason scores of ≤6 had a pathogenic variant; compared with 15.4% of those with scores of ≥7
In terms of guidelines evaluation, per the authors, only 126 (63%) patients with positive results were eligible for genetic testing based on currently available NCCN guidelines, whereas 73 (37%) would not have qualified.
Based on this, they suggest that current testing guidelines are inadequate to capture all mutations.
Limitations:
1. This is a study partially completed by companies with vested benefit in testing every patient. Their bias towards global testing cannot be ignored.
2. Unfortunately, it is not clear how they had enough data to know if men had family history to meet the criteria for testing per NCCN guidelines. This needs to be clarified.
Discussion Points:
While the guidelines may be inadequate to capture all mutations, unfortunately this does not always correlate to altered clinical outcomes. Until better data is available regarding the clinical sequelae of each of these mutations, it is not necessarily cost-effective to screen every patient. Furthermore, without understanding the implications of the 25% of gene mutations identified that were not on the hereditary gene panel, it would be unsafe to test every patient.
Presented By: Piper L.W. Nicolosi
Co-Authors: Scott T. Michalski, Brandy Freschi, Erin O'Leary, Rita Quintana, Ian Wilson, Martin P. Powers, Oliver Sartor
Institution(s): Invitae, San Francisco, CA; MPP, New York, NY; Tulane University School of Medicine, New Orleans, LA
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
Reference:
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2017). nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf