Should Patients With a Family History of Cancer Be Excluded From Active Surveillance?

In a recent report published in the Journal of Urology, Jibara et al¹ examined the association between family history of prostate cancer (FHP), or family history of cancer (FHC), and the risk of progression or adverse pathology after radical prostatectomy following active surveillance (AS). Prostate cancer is the most common non-dermatological cancer in men, with ~1.4 million men diagnosed worldwide annually, and more than 200,000 new cases diagnosed each year in the United States. Within this group of men is a subset with a well-known hereditary component of prostate cancer.

Potential Germline Mutations

The so-called hereditary cancer syndromes (HCS) continue to be investigated, and the role they play in prostate cancer is becoming better understood. For instance, BRCA1 and BRCA2 germline mutations, previously so closely associated with aggressive breast cancer, now are also understood to be involved in many other cancer-development processes. In particular, BRCA2 is associated with an increased risk of aggressive and early prostate cancer with worse outcomes. At the same time, there has been a rapid development of novel cancer drugs aimed at treating germline mutations such as BRCA2.

As we gain greater understanding of the mutations that occur, and the targeted therapies available for these mutations, it becomes even more important to identify a patient’s genomic profile as early as possible. This is true for nearly all types of cancer, and is particularly useful for men with prostate cancer. Familial prostate cancer typically is associated with high-risk disease, although there are many men undergoing AS for low- or favorable intermediate-risk disease who have a known BRCA1 or BRCA2 mutation.

The presence of these mutations in the AS population has been associated with upstaging. There have been numerous other germline mutations described in the AS cohort that indicate increased risk and a need for definitive treatment. Despite these known risks, the relatively low yield and high cost of genetic testing for men with low- or intermediate-risk prostate cancer has led to the current recommendation to limit genetic testing to patients with high-risk prostate cancer based on disease stage, FHP, or FHC. Jibara et al retrospectively reviewed approximately 20 years of data at a tertiary cancer center, to evaluate the oncologic impact of a strong FHP or FHC after AS concludes with definitive prostatectomy.

Assessing FHP and FHC

The researchers assessed the impact of a strong FHP or FHC, as defined by leading cancer care organizations. FHP was defined as 1 or more first-degree relatives with prostate cancer, or 2 or more first- or second-degree relatives with prostate cancer. FHC was defined as 3 or more family members on the same side of the family with cancer of various primary organs. The researchers assessed whether there was an association between patients with FHP or FHC and time to progression on AS, which they defined as any pathologic upstaging on biopsy.

The study population included approximately 3200 men on AS in their cohort; 669 (21%) had FHP, 34 (1.1%) had FHC, and 95 (3%) had both FHP and FHC. There was a significant association between family history and prostate cancer progression while on AS. Men with a strong FHP had an increased risk of progression compared to men with no FHC. Of note, there was no meaningful difference between having both FHC and FHP versus having FHP alone. Nearly 500 men on AS underwent radical prostatectomy, and more than 200 were found to have adverse pathology on final pathologic review — defined as upgrading from preoperative biopsy, extraprostatic extension, seminal vesicle invasion, or lymph node involvement. However, there was no association between upstaging and adverse pathology after prostatectomy in men with FHP or FHC.

Study Limitations

The researchers stressed that despite an increased rate of progression found in men with FHP upon surveillance biopsy, the clinical significance of the finding remains unclear, particularly as there was no association between increased adverse pathology upon definitive treatment and radical prostatectomy. They also noted that a patient’s family history could sway a clinician’s decisionmaking process, potentially altering the prescribed surveillance frequency or even lowering the threshold for recommending definitive treatment. Such decision bias is unavoidable in the clinical setting, but it is not supported by the findings of researchers. In the published literature, numerous other studies also demonstrate no association between FHP and pathologic upgrading or adverse pathology upon eventual radical prostatectomy.

As a limitation of the study, the researchers noted that no two AS protocols are the same, particularly because guideline recommendations and surveillance protocols change, and triggers for intervention are altered. It is also worth noting that progression to definitive treatment with prostatectomy is not a standard outcome measure, and it is affected by a variety of subjective factors, such as a patient or clinician’s decision to change their mind about the treatment course.

Investigation into FHP and FHC remains a growing area of interest for prostate cancer management. Although previously only part of the recommended management algorithm for patients with high-risk disease, Jibara et al offer insights into how a patient’s family history may impact their experience on an AS protocol.

Further investigation remains warranted to assess the clinical significance and association of germline mutations and disease outcome in men with low-risk or favorable intermediate-risk prostate cancer who are pursuing AS as a treatment modality. Until then, the authors conclude that there is no indication to use family history as a contraindication for AS, particularly in patients with no previously identified genetically defined cancer syndrome. As the field of genomics gains further traction in the clinical arena, we can expect such conundrums to increase in frequency, even as patients gain benefit from our improved understanding of their individual risks.

Reference

1. Jibara GA, Perera M, Vertosick EA, et al. Association of family history of cancer with clinical and pathological outcomes for prostate cancer patients on active surveillance. J Urol. 2022;208(2):325-332. doi: 10.1097/JU.0000000000002668