For Australian men, has a family history of prostate cancer been shown to be reliably associated with a 2.0-fold or greater increase in risk of occurrence of or death from prostate cancer when compared to men who do not have a family history of prostate cancer? (PICOi question 1)ii
Guidelines developed in partnership with
Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Clinical practice guidelines PSA Testing and Early Management of Test-Detected Prostate Cancer. Sydney: Cancer Council Australia. [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=122822, cited 2019 Feb 20]. Available from: https://wiki.cancer.org.au/australia/Guidelines:PSA_Testing/Risk.
National Health and Medical Research Council
In approving the guidelines (recommendations), NHMRC considers that they meet the NHMRC standard for clinical practice guidelines. This approval is valid for a period of five years. NHMRC is satisfied that the guidelines (recommendations) are systematically derived, based on the identification and synthesis of the best available scientific evidence, and developed for health professionals practising in an Australian health care setting.This publication reflects the views of the authors and not necessarily the views of the Australian Government.
In order to help men who are considering prostate-specific antigen (PSA) testing to make an informed decision and tailor their choices based on individual risk, it is necessary to assess factors associated with an increased risk of diagnosis of, or death from, prostate cancer. While many modifiable and non-modifiable risk factors for prostate cancer have been investigated, few have been clearly shown to be strongly associated with increased risk. Fewer studies still have specifically assessed the risks for Australian men.
This chapter only considers family history as a risk factor for prostate cancer. Family history was considered because it is common for PSA testing guidance to recommend that men who have a family history of prostate cancer, and who decide to be tested, should commence testing at a younger age (usually 40 or 45) than men without a family history. Other risk factors, such as ethnicity, will be considered in future editions of this guideline.
PSA testing strategies in high-risk groups outlines an approach that can be applied to any risk factor.
- 1 Background
- 2 Evidence
- 2.1 Prostate cancer diagnosis
- 2.2 Prostate cancer-specific mortality
- 2.3 Interpreting the findings
- 3 Evidence summary and recommendations
- 4 Discussion
- 5 Footnotes
- 6 References
Family history of prostate cancer with onset younger than 65 years has been found to be associated with an increased risk of prostate cancer in a number of international cohorts. The risk appears to increase with the ‘level’ of family history, based on factors such as the age at which family members were diagnosed, the relationship (brothers and/or father) and the number of affected relatives. Family history is one of the main risk factors used by health professionals in the Australian primary care setting when assessing risk of prostate cancer and informing men of their risk. A number of international guidelines on prostate cancer screening recommend that men with a family history of prostate cancer commence the informed decision making process or testing at an earlier age than men at average risk of prostate cancer (i.e. men without a family history).
The PSA level of a man’s first PSA test is also associated with subsequent risk of prostate cancer. It has been suggested that baseline PSA testing for men in their forties is a useful way of identifying men who are at high risk of prostate cancer. The evidence for PSA level as a risk factor is reviewed in Chapter 2 (see Using a PSA test result at a particular age to inform subsequent PSA testing).
Chapter 2 includes PSA testing recommendations relating to family history of prostate cancer and to PSA as a risk factor for prostate cancer.
Eleven retrospective cohort studies  and one nested case-control study addressing the question and meeting the inclusion criteria were included in the systematic review: three used linked population-wide data from Sweden, five used the Swedish Family-Cancer Database, and one each used linked data from Utah in the USA, Southern Sweden, Iceland, and Finland. The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
All 11 retrospective cohort studies  (level III-2 evidence) that reported the risk of incident prostate cancer were of low quality, with a high risk of bias due to inadequate length of follow-up for the diagnosis of prostate cancer and inadequate control for potential confounding factors. Notably, none controlled for potential PSA testing bias resulting from the fact that men who have a close relative diagnosed with prostate cancer may be more likely to request a PSA test and then be diagnosed with prostate cancer. Similarly, the nested case-control study (level II evidence) was also low quality with a high risk of bias.
Three of the retrospective cohort studies also reported the risk of death from prostate cancer. These studies were assessed to be low quality with a high risk of bias, due to an inadequate length of follow-up.
Prostate cancer diagnosis
The results were very consistent across studies that assessed risk of a prostate cancer diagnosis for men with a particular level of family history. Two studies  that assessed family history in third-degree relativesiii each reported a relative risk (RR) of approximately 1.2, with 95% confidence intervals that included 1 or had a lower limit close to 1. For family history in second-degree relatives, the same two studies reported RRs of 1.3–1.4 and 1.7 (with a lower 95% confidence limit below 1) when the affected relative was diagnosed before age 55–60 years.
For men with affected first-degree relatives, the RRs were generally greater than 2.0 (which is considered clinically important) and statistically significant. Men with a first-degree relative (father or brother) diagnosed with prostate cancer had approximately double the risk of being diagnosed with prostate cancer, compared with men without this family history or the general male population. The RR was higher for men aged less than 50–55 years, those whose first-degree relative was diagnosed before age 68 years and those with multiple affected first-degree relatives. While there was some inconsistency across studies, the increased risk was less than 2.0-fold for those aged approximately 75–80 years or over.
The observed association between family history and the probability of being diagnosed with prostate cancer may be affected by increased PSA testing in the exposed group. None of the studies directly addressed the potential impact of increased PSA testing of asymptomatic men with a positive family history. Data from the population-based Prostate Cancer Database Sweden reported stronger associations between family history and diagnosis of Stage 1c prostate cancer (which is detected after a PSA test) and diagnosis closer to the time of that of the family member (within 1 year). In all but one of the studies reviewed, the period of observation for the diagnosis of prostate cancer fell within the PSA testing era (after 1990).
Because of this potential confounding by PSA testing of the association between family history and diagnosis of prostate cancer, it may be misleading to use the RRs of prostate cancer incidence in men with a family history to determine whether a change in the testing protocol is warranted (see Chapter 2 Testing). Studies that report RRs based on prostate cancer-specific mortality rates are probably more reliable, although a small negative bias might be expected from the likely protective effect of PSA testing against prostate cancer death. Therefore in this review, we have focused on the estimates of the RR for death from prostate cancer for men with a family history.
Prostate cancer-specific mortality
Three studies reported the association between risk of death from prostate cancer and levels of family history (Table 1.1). Men whose fathers had been diagnosed with prostate cancer were approximately twice as likely to die from prostate cancer, compared with men without a first-degree relative diagnosed with prostate cancer. Men with a brother diagnosed with prostate cancer were at 2.8-fold increased risk of dying from prostate cancer, and this increased to 3.3-fold when the brother was diagnosed before age 60 years.
The risk of dying from prostate cancer was higher when two first-degree relatives were diagnosed: the risk was 3 times higher for men with a father and a brother diagnosed with prostate cancer, 6 times higher if two brothers were diagnosed with prostate cancer, and 7 times higher for men whose father and a brother had died from prostate cancer. The risk of dying from prostate cancer was 8–10 times higher for men with three first-degree relatives diagnosed with prostate cancer.
In summary, men with first-degree relatives (father and/or brother/s) diagnosed with prostate cancer had at least double the risk of dying from prostate cancer than men without this family history. The relative increase in risk was greater when multiple first-degree relatives were affected, especially multiple brothers, when a brother was diagnosed before age 60 years, or when both the father and a brother had died from prostate cancer.
Table 1.1. Relative risk of dying from prostate cancer for men with a first-degree relative diagnosed with prostate cancer, compared with those without a first-degree relative diagnosed with prostate cancer or the general male population
Interpreting the findings
None of the studies were conducted in Australia. The generalisability and applicability of their findings to the Australian setting may be affected by a number of factors, including the degree to which PSA testing is used for screening asymptomatic men, and genetic factors (the majority of studies were conducted in Sweden). In addition, differences in the patterns of prostate cancer treatment may affect prostate cancer-specific mortality rates.
The effect of family history on the risk of prostate cancer-specific mortality is considered in Chapter 2.
Evidence summary and recommendations
| Risk of prostate cancer diagnosis
Men with a first-degree relative (father or brother) diagnosed with prostate cancer had approximately double the risk of being diagnosed with prostate cancer than men without this family history.
This RR was higher for younger men, those whose first-degree relative was diagnosed at a younger age, and those with multiple first-degree relatives diagnosed with prostate cancer.
While there was some inconsistency across studies, the RR was less than 2 for those aged approximately 75–80 years or over. The RR was 1.3–1.4 for men with only second- or third-degree relatives diagnosed with prostate cancer.
Uncontrolled confounding by PSA testing is likely to bias estimates of RR of prostate cancer incidence upwards.
|II, III-2||, , , , , , , , , , , |
| Risk of death from prostate cancer
Men with a first-degree relative (father or brother) who was diagnosed with prostate cancer had a 2- to 3-fold increased risk of dying from prostate cancer compared with men without this family history.
Compared with no family history, the RR of death from prostate cancer was 6- to 10-fold greater if multiple first-degree relatives were diagnosed with prostate cancer (two or three brothers, or two brothers and father), or if the brother and father had died from prostate cancer.
|III-2||, , |
Note on the recommendations based on this evidence
No direct recommendations were formulated based on this evidence because it serves to identify risk, not to evaluate the effects of interventions to manage this risk. This evidence on risk informed the recommendations in Chapter 2.
PSA testing strategies in high-risk groups includes a consensus-based recommendation for PSA testing of men whose risk of prostate cancer is estimated to be at least 2.5–3 times higher than average and for men whose risk is estimated to be at least 9–10 times higher than average due to any risk factors, including family history. No separate recommendation was made about PSA testing in men with risk factors that increase risk by a factor of less than 2.5–3 times average risk. The Expert Advisory Panel considered that this lesser degree of risk may not be sufficient to justify a change in the evidence-based PSA testing strategy recommendation for men at average risk, after taking into consideration the need to balance the potential benefits and harms of PSA testing.
i Clinical questions were translated into the PICO framework: population, intervention (or exposure), comparator and outcome (see Appendix 3).
ii For the current edition of this guideline, the scope of this clinical question was limited to family history. At the next edition, this systematic review will be updated and expanded to include other risk factors such as genetic factors (e.g. BCRA1, BCRA2, HOXB13 G84E, Lynch syndrome genes).
iii First-degree relatives comprise fathers, brothers and sons. Second-degree relatives include grandfathers, uncles, nephews and grandsons. Third-degree relatives include cousins and great-grandfathers.
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