Family history and prognosis of prostate cancer

Background: Prostate Cancer (PCa) is the second most common malignancy among men in the world. In Sweden about 10,000 new cases are diagnosed each year. Mortality rates have been rather stable but have declined the past decades due to early diagnosis and treatment at the expense of overtreatment. High age, ethnic origin and family history are known risk factors. The strongest predictor for poor prognosis is tumour differentiation at diagnosis. Previous studies have suggested that men with family history of mortal PCa, themselves are at higher risk for mortal disease. In twin studies it has been demonstrated that the contribution of shared genome to PCa risk is substantial.

Aims: The overall aim is to explore the importance of family history as a prognostic marker for prognosis in PCa. Specifically, in Paper I: To estimate the concordance of tumour differentiation among pairs of brothers with PCa. Paper II: To estimate the relative differences in risk of non-low PCa between different types of brothers. Paper III: To estimate if men with family history of PCa have higher risk of postoperative histopathological upgrading or upstaging comparted to men without family history. Paper IV: To evaluate the prognostic value of the HOXB13 G84E mutation in a screening cohort.

Methods: PCBaSe provides a population-based database with the National Prostate Register (NPCR) linked to several other National registers in Sweden. In Paper I 1,022 pairs of brothers with PCa diagnosed 1996-2006 were identified. The relative risk for the second brother to be concordant in tumour differentiation (Gleason score) was estimated with SIR. In Paper II 4,262 pairs of brothers with PCa diagnosed 1996-2012 were identified. Using the Swedish twin register and the Multi-Generation Register, all pairs of brothers were stratified by type of fraternity. Tumour characteristics were compared and the risk of concordance for non-low risk PCa was estimated. In Paper III, 6,638 men with low risk PCa treated with prostatectomy 2003- 2012 were identified. Of those, 1,696 (26%) had family history of PCa among FDRs. The excess risk of postoperative upgrading or upstaging was estimated using logistic regression comparing men with and without family history of PCa. In Paper IV the study population was based on a screening cohort in Stockholm County 2012-2015. 27,578 men with Prostate Specific Antigen (PSA) >1 were offered genetic testing with 232 Single Nucleotide Polymorphisms (SNPs) associated with PCa. Men with PSA>3 were offered biopsies. Carriers of HOXB13 G84E were compared to non-carriers for risk of significant PCa.

Results: In Paper I, we found an overall risk of concordance in tumour differentiation of SIR 3.1 (95% CI, 2.9–3.3). SIR for brothers of men with high grade Gleason score was 4.00 (95% CI, 2.63–5.82). In Paper II, the adjusted OR for concordance in non-low risk PCa among monozygotic twins was 3.85 (95% CI, 0.99-16.72) and for full brothers adjusted OR was 1.21 (95% CI, 1.04-1.39). In analyses restricted to pairs of brothers diagnosed within 4 years, the results were similar. In Paper III, the risk of postoperative upstaging among men with first- degree relatives (FDR's) with high grade or lethal PCa was OR 1.06 (95% CI, 0.76-1.47). For risk of upgrading, OR was 1.17 (95% CI, 0.91-1.50). In Paper IV, the prevalence of HOXB13 G84E was 1.3% of 27,578 men with PSA between 1 and 100. The overall risk of any cancer for HOXB13 G84E carriers was OR 4.67 (95% CI, 2.93-7.73). The risk for clinically significant cancer was OR 2.10 (95% CI, 1.34-3.26).

Conclusions: Men with brothers with high grade PCa are at higher risk themselves for high grade PCa, which have an impact on counselling these men. Shared genetic factors seem to increase the risk of non-low risk PCa. The highest increase in risk is observed among monozygotic twins, although with non-significant estimate. Men with familial history of high risk or lethal PCa are not at higher risk of postoperative upstaging or upgrading after prostatectomy for low risk PCa, compared to men without family history. Those men can comfortable be recommended active surveillance on the same basis as men without family history. Carriers of the rare HOXB13 G84E mutation are increased risk for clinically significant and HOXB13 G84E and we argue that HOXB13 G84E should be included for men recommended genetic counselling.

List of scientific papers

I. Concordance of tumor differentiation among brothers with prostate cancer. Jansson KF, Akre O, Garmo H, Bill-Axelson A, Adolfsson J, Stattin P, Bratt O. EUROPEAN UROLOGY. 62 (2012) 656–661.
https://doi.org/10.1016/j.eururo.2012.02.032

II. Concordance of Non-Low-Risk Disease Among Pairs of Brothers With Prostate Cancer. Jansson F, Drevin L, Frisell T, Stattin P, Bratt O, Akre O. Journal of Clinical Oncology. 36:1847-1852. 2018.
https://doi.org/10.1200/JCO.2017.76.6907

III. Risk of Postoperative Upstaging or Upgrading Among Men with Low- Risk Familial Prostate Cancer. Jansson F, Folkvaljon F, Stattin P, Bratt O, Akre O. The journal of urology. 2020, Vol.204(1), p.79-81.
https://doi.org/10.1097/JU.0000000000000793

IV. Prevalence of HOXB13 G84E mutation and its association to prostate cancer in a population-based screening cohort. Jansson F, Eklund M, Akre O, Aly M, Egevad L, Wiklund F, Grönberg H, Nordström T. [Manuscript]