JU INSIGHT Impact of Family History and Germline Genetic Risk SNPs on Long-Term Outcomes of Favorable-Risk Prostate Cancer

By: Florian Rumpf, MD, Massachusetts General Hospital, BostonUniversity Hospital Wuerzburg, Germany; Anna Plym, PhD, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, Brigham and Women’s Hospital, Boston, Massachusetts, Karolinska Institutet, Stockholm, Sweden; Jane B. Vaselkiv, MPH, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Kathryn L. Penney, PhD, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; Mark A. Preston, MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts; Adam S. Kibel, MD, Brigham and Women’s Hospital, Boston, Massachusetts; Lorelei A. Mucci, ScD, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Keyan Salari, MD, PhD, Massachusetts General Hospital, BostonCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Broad Institute of The Massachusetts Institute of Technology and Harvard, Cambridge | Posted on: 18 Jun 2024

Rumpf F, Plym A, Vaselkiv JB, et al. Impact of family history and germline genetic risk single nucleotide polymorphisms on long-term outcomes of favorable-risk prostate cancer. J Urol. 2024;211(6):754-764. doi:10.1097/JU.0000000000003927

Study Need and Importance

Prostate cancer prognosis is heterogeneous, even among those classified with localized, favorable-risk disease. We aimed to elucidate the combined impact of family history and germline genetic risk single nucleotide polymorphisms on long-term outcomes in this patient population. This study addresses the critical need for personalized risk stratification tools to guide clinical decision-making among individuals with favorable-risk prostate cancer considering active surveillance vs treatment.

What We Found

Our study revealed compelling insights into the prognostic significance of family history and germline genetic risk single nucleotide polymorphisms among patients with favorable-risk prostate cancer. Notably, individuals with a positive family history of prostate, breast, or pancreatic cancer exhibited a substantially elevated risk of prostate cancer-specific death. Furthermore, the rs2735839 germline risk allele on chromosome 19q13 was independently associated with increased mortality risk, whereas a prostate cancer polygenic risk score was not. Importantly, the combined presence of a positive family history and the rs2735839 risk allele demonstrated an additive effect on the risk of dying of prostate cancer (Figure).

Figure. Survival curves from the Aalen-Johansen estimator for prostate cancer–specific death, stratified by the number of heritable risk factors, among participants with National Comprehensive Cancer Network (NCCN) low- and favorable intermediate-risk prostate cancer (n = 1367; A) and the subgroup of participants with NCCN low-risk prostate cancer (n = 896; B).

Limitations

Several limitations warrant consideration. Our study population comprised predominantly White participants from the Health Professionals Follow-up Study, limiting generalizability to more diverse populations. Additionally, while we focused on favorable-risk prostate cancer, the influence of family history and genetic variants may differ across risk categories and treatment modalities. Finally, rare germline pathogenic mutations (eg, BRCA2) were not assessed in the study population, which are expected to affect a small number of patients but would potentially further enhance risk assessment.

Interpretation for Patient Care

The integration of family history assessment and germline genetic testing into clinical practice holds significant promise for refining risk stratification and individualizing treatment approaches in favorable-risk prostate cancer. Our findings underscore the importance of incorporating familial cancer history and specific genetic variants, such as rs2735839, into risk assessment tools to optimize patient outcomes.