Review: Association of Family History of Cancer With Clinical and Pathological Outcomes for Prostate Cancer Patients on Active Surveillance

By David Ambinder, MD - September 27, 2022

Should a family history of prostate cancer influence consideration of a patient’s candidacy for active surveillance? Researchers at Memorial Sloan Kettering Cancer Center in New York attempted to answer this question in their retrospective investigation of patients in a large active surveillance database.1 Their goal was to examine the association between a family history of prostate cancer, or other cancers with disease progression or adverse pathology in patients whose prostate cancer was managed through active surveillance.

Despite the documented association between a family history of prostate cancer and the risk of developing the disease, there are fewer data available for prostate cancer compared with other well-known hereditary syndromes. In recent years, however, emerging genetic data—including data on the BRCA2 germline mutation that is associated with development of earlier-onset and more aggressive prostate cancer2,3—have shown a correlation between family history and worse pathological and oncologic outcomes.4 The authors noted a 2019 study that found the presence of a BRCA1 or BRCA2 mutation was associated with upstaging in patients on active surveillance protocols5 and a study published in early 2022 that found other germline variants associated with prostate cancer were positively correlated with risk for conversion of patients on active surveillance to treatment with definitive therapies.6

Although current recommendations differ slightly in their definitions of patient populations most likely to benefit from testing, they agree that testing typically benefits the patient with a family history of disease or high-risk disease stage. However, identifying family history criteria for germline testing may be important for patients with low-risk disease or on active surveillance.

A New Study for Family History of Prostate Cancer

Patients included in the study were in Gleason grade group 1 or 2 over a 20-year period from 2000 to 2019. Family history of cancer and family history of prostate cancer were defined by criteria from the 2019 National Comprehensive Cancer Network® (NCCN®) guidelines for prostate cancer and other commonly used guidelines. Family history of prostate cancer was self-reported and defined as ≥1 first-degree relative with prostate cancer or ≥2 first- or second-degree relatives with prostate cancer. Family history of cancer was also defined by the NCCN guidelines as ≥3 family members on the same side of the family diagnosed with melanoma or bile duct, breast, colorectal, endometrial, gastric, kidney, ovarian, pancreatic, prostate, small bowel, or urothelial cancer.

The authors considered that ascertainment bias may be introduced when patients have a family history of cancer or prostate cancer. Therefore, part of their analysis was designed to evaluate if patients in these populations underwent more surveillance while on active surveillance, compared with those who had no family history. They focused on whether a strong family history of cancer or prostate cancer was associated with time to progression (ie, upgrading Gleason grade group on biopsy) while on active surveillance. Patients who initiated surgical, radiation-based, focal, or chemotherapy/hormonal therapy without having shown progression on biopsy were censored on the date of commencing treatment.

After eligibility and exclusion criteria were met, 3211 patients on active surveillance were included in the study: of these 21% (n=669) met the criteria for a family history of prostate cancer, 1.1% (n=34) had a family history of other cancer, and 3% (n=95) fit the criteria for a family history of cancer and prostate cancer. A total of 23.5% of patients progressed on active surveillance. The authors found that patients with a family history of cancer or prostate cancer were not more frequently followed while on active surveillance and did not undergo a statistically significant increase in the frequency of prostate biopsy or magnetic resonance imaging (MRI) compared to patients with no family history.

The Correlation Between Family History and Risk of Progression

The authors reported that there was a statistically significant association between a strong family history of prostate cancer and risk of progression on active surveillance (hazard ratio, 1.31; 95% CI, 1.11-1.55; P=0.002). This was not true for patients with a family history of other cancer or patients with a family history of both cancer and prostate cancer. After adjusting for age, Gleason grade group, and prostate-specific antigen level at the time of diagnosis, patients with a family history of prostate cancer had a 48% risk of progression over 10 years on active surveillance (95% CI, 42-53) compared to a 39% risk for patients with no family history of cancer or prostate cancer (95% CI, 36-42). In patients who had undergone a radical prostatectomy, a family history of cancer or prostate cancer was not associated with a higher risk for adverse pathology.

In their discussion, the authors stated that they found a slight statistically significant increase in the risk of progression for patients on active surveillance who had a family history of prostate cancer. However, they cautioned that, given the small difference between the study groups and the wide confidence intervals in their findings, the clinical importance of these results remains unclear. They also noted that while having a family history of cancer or prostate cancer was not associated with undergoing more frequent MRI study or more frequent biopsies, they did not assess whether patients were more likely to undergo surgical treatment. Their findings of no association between family history of prostate cancer and pathological upgrading or adverse pathology are consistent with previous studies,7 as are their similar findings regarding patients with a family history of other cancer.8

Based on their results, the authors suggest that “patients with a family history of cancer per the authoritative guidelines may be suitable for active surveillance due to the low risk of progression to curative treatment and adverse pathology on definitive radical prostatectomy…in the absence of a known genetically defined hereditary cancer syndrome, family history of prostate cancer and or cancer should not be used as a sole trigger to preclude patients with low risk disease to active surveillance protocols.” There remains a significant need, however, for further research evaluating the association of germline mutations with disease outcome in patients treated with active surveillance.

 

References

  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.
  2. Nyberg T, Frost D, Barrowdale D, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2020;77(1):24-35. doi: 10.1016/ j.eururo.2019.08.025.
  3. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi: 10.1200/JCO.2012.43.1882.
  4. Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022.
  5. 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;75(5):743-749. doi: 10.1016/j.eururo.2018.09.021.
  6. Jiang Y, Meyers TJ, Emeka AA, et al. Genetic factors associated with prostate cancer conversion from active surveillance to treatment. HGG Adv. 2022;3(1):100070. doi: 10.1016/j.xhgg.2021.100070.
  7. Selkirk CG, Wang CH, Lapin B, Helfand BT. Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease. Urology. 2015;85(4):742-747. doi: 10.1016/j.urology.2014.10.060.
  8. Herkommer K, Maier N, Ankerst DP, Schiele S, Gschwend JE, Meissner VH. No detrimental effect of a positive family history on postoperative upgrading and upstaging in men with low risk and favourable intermediate-risk prostate cancer: implications for active surveillance. World J Urol. 2021;39(7):2499-2506. doi: 10.1007/s00345-020-03485-5.
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