Dr. Schaeffer notes that providers screening and treating localized prostate cancer should care about genetics because of (i) augmenting risk stratification through the integration of genetics, and (ii) heritable genetic alterations can impact the management of localized prostate cancer. Specifically, three inherited factors can impact a man’s risk of being diagnosed with prostate cancer, including family history, rare pathologic variants, and polygenetic risk/single nucleotide polymorphisms.
Family history is the oldest and most established risk factor for prostate cancer, which is generally defined as three or more relatives with prostate cancer or two or more relatives with early-onset prostate cancer (age less than 55 years). Overall, 10-15% of men with prostate cancer report a first-degree relative affected by prostate cancer, with the relative risk varying between 2.2 and 7.7. There are several risk dependent factors, including: (i) affected first-degree relative (father vs brother, RR 2.2 vs 3.4), (ii) number of affected relatives (one vs three relatives, RR 2.5 vs 7.7), (iii) relationship to affected relative (first, second, or third-degree), and (iv) pathologic feature of affected relative (low grade vs high grade, RR 2.53 vs 4.00). Additionally, a family history in black men is associated with increased tumor aggressiveness.
To summarize his discussion of family history, Dr. Schaeffer notes:
- Family history is an important heritable risk factor for the development of prostate cancer across different racial and ethnic backgrounds
- Impact of heredity depends on age of diagnosis, number of affected relatives, closeness of relatives, and aggressiveness of the disease
- It is very cost-effective
- Family history does blend genetic and environmental factors
Dr. Schaeffer notes that there are rare pathologic variants associated with increased risk of prostate cancer, including BRCA1, BRCA2, Lynch Syndrome (MSH 1, 2, 6), and HoxB13. For BRCA1, a meta-analysis suggests a moderate association between BRCA1 mutations and prostate cancer risk, with a pooled odds ratio of 1.35 (95% CI 1.03-1.76)1. The same meta-analysis assessing BRCA2 notes that the association between this mutation and prostate cancer has a pooled odds ratio of 2.64 (95% CI 2.00-3.45). EMBRACE is a UK-based cohort study of BRCA1/2 carriers identified in clinical genetic centers in the UK and Ireland starting in 1998 (n=376 BRCA1, n=447 BRCA2). This population has been prospectively followed with variable screening regimens for prostate cancer, with BRCA1 and BRCA2 carriers having increased standardized incidence ratios of being diagnosed with prostate cancer compared to the general population. However, when compared to men in the ERSPC, BRCA2 carriers had an increased risk of prostate cancer, whereas BRCA1 carriers did not.
Lynch Syndrome results in non-polyposis colon cancer, however, there are extra-colonic sites that are affected, including urothelial and renal diseases. Several studies have also suggested that there may be an increased risk of prostate cancer among those with Lynch Syndrome, specifically those with MMR mutations, however, most people believe that additional studies are required before routine intense screening occurs for prostate cancer for Lynch Syndrome patients. HoxB13 is a developmental gene-regulating androgen receptor target that is associated with earlier onset prostate cancer, but there has been no association with more aggressive disease.
To summarize his discussion of rare pathologic variants, Dr. Schaeffer notes:
- Rare pathologic variants are rare, with only 1 in 400 to 1 in 500 for patients with BRCA1 mutations
- BRCA2 carriers have a higher risk of aggressive prostate cancer
- Consistent screening can detect these cancers while they are in a curable, localized state (ie. annual PSA screening with biopsy recommended when PSA is >3.0 ng/mL)
- There is limited information on diverse racial or ethnic populations
Single nucleotide polymorphisms (SNPs) are associated with an increased risk of prostate cancer, and multiple studies have described prostate cancer-associated SNPs. Additionally, several of these studies have demonstrated that the integration of SNPs with PSA-based screening can improve an individual’s relative cancer risk. In a multi-ancestry meta-analysis of prostate cancer genome-wide association studies, including 107,247 cases and 127,006 controls, Conti et al.2 identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total of known risk variants to 269. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% CI, 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry:
Retrospective series of outcomes of patients with BRCA1/2 mutations generally have a limited number (<100 men) of germline BRCA1/2 cases. These men are generally more likely to have a higher grade and stage of disease and more likely to have pathologic lymph nodes and metastases at diagnosis than prostate cancer non-carriers. Although active surveillance is generally very safe for men with low-risk disease, the safety of surveillance in men with rare pathologic variants has been questioned. Among 1,211 men on active surveillance, Carter et al.3 found that 289 patients experienced grade reclassification, including 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers (HR for reclassification 1.96, 95% CI 1.004-3.84). Additionally, reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers (HR 2.74, 95% CI 1.26-5.96).
Dr. Schaeffer concluded his presentation with the following take-home messages:
- Family history is important, with consideration of testing for rare pathologic variants
- Genomic risk score is promising and in need of prospective evaluation
- BRCA2 carriers have a higher risk of reclassification in active surveillance
- BRCA2 carriers with higher-grade disease appear to have a slightly more aggressive disease course
Written By: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021
- Oh M, Alkhushaym N, Fallatah S, et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate. 2019 Jun;79(8):880-895.
- Conti DV, Darst BF, Moss LC, et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet. 2021 Jan;53(1):65-75.
- Carter HB, Helfand B, Mamawala M, et al. Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. Eur Urol 2019 May;75(5):743-749.