1.Recreational activity and prostate cancer specific mortality

Several studies have suggested that higher levels of physical activity are associated with a lower risk of dying from colorectal or breast cancer. This has also been highlighted for prostate cancer, although the potential for reverse causation bias – that ill health was the cause of lower physical activity - has limited interpretation of these results.

A study published in European Urology this month revisited this topic and analysed the recreational activity of 10,864 men, to examine the reported association of pre- and post-diagnosis physical activity with prostate cancer specific mortality. The study focused on aerobic exercise and the amount of physical activity per week during the past year was self-reported via questionnaire. Pre-diagnosis physical activity was calculated from the last questionnaire completed at least 1 year prior to diagnosis, and the post-diagnosis activity calculated from the first questionnaire completed at least 1 year after diagnosis. The median age at diagnosis was 71 years (interquartile range: 67-75 years), and deaths were ascertained from the national death index. To reduce reverse causation bias, deaths occurring within four years of the post-diagnosis questionnaire were excluded.

Pre-diagnosis physical activity was taken as a surrogate measurement of long-term physical activity (n=7328). When controlling for age, cancer status, family history, race and lifestyle factors (including PSA test history, BMI, smoking status and diet) there was a statistically significant inverse association between prediagnosis recreational physical activity and prostate cancer specific mortality amongst men with low-risk tumours (p=0.03). Furthermore, men with low-risk tumours who walked for more than 7 hours per week had a 47% less risk of prostate cancer specific mortality compared with those who walked 1-3 hours per week (HR: 0.53, 95% CI: 0.33-0.86), p=0.04). High levels of physical activity were also associated with a 20% lower risk of cardiovascular disease specific mortality (HR: 0.80, 95% CI: 0.67-0.96, p=0.008) and a 12 % lower risk for all-cause mortality (HR: 0.88, 95% CI: 0.80-0.97, p<0.0001).

When adjusted for treatment, family history, cardiovascular disease history, smoking status, BMI, age and PSA test frequency, high levels of post-diagnosis recreational activity were associated with a significantly lower risk of prostate cancer specific mortality (HR: 0.69, 95% CI: 0.49-0.95, p=0.006) (n=5309), and were also associated with a 14% lower risk of all-cause mortality (HR:0.86, 95% CI: 0.75-0.98, p<0.0001).

Limitations of this study include potential measurement error from one-time self-reported physical activity, and positive confounding by severity of disease at diagnosis cannot be excluded. Also, a lack of information on treatment completion date, adverse effects from treatment, adjuvant therapies and tumour recurrence limited analysis control. However, the study supports the importance of ongoing and future clinical trials to assess impact of physical activity on tumour progression.

2: The effect of family history of prostate cancer on disease outcomes following radical prostatectomy

Approximately 2.6% of all prostate cancer patients and 11.5% of patients with a family history are considered to have hereditary prostate cancer (defined as a subgroup of familial prostate cancer with a likelihood of genetic predisposition), using the John Hopkins criteria for diagnosis. It is generally agreed that a family history of prostate cancer is associated with an increased risk of disease and an earlier onset of diagnosis. However, it is less clear whether hereditary prostate cancer confers worse outcomes when compared with sporadic prostate cancer. Conflicting results have potentially been caused by differing definitions and inclusion criteria of ‘family history’. Furthermore, some studies have classified patients as sporadic cases in the absence of a complete medical history of first-degree relatives.

A study reported this month in the World Journal of Urology analysed the data of 11,654 patients taken from the German Familial Cancer Database, to establish whether family history has an effect on the presentation of prostate cancer at diagnosis and clinical outcomes following radical prostatectomy.

The study focused on the two extreme ends of the family history spectrum: sporadic prostate cancer (SPC) and hereditary prostate cancer (HPC). SPC was defined as having two or more brothers over the age of 60 with no family history of prostate cancer, and HPC defined according to John Hopkins’ criteria, with at least one of the following: over three affected relatives within any nuclear family (father and two brothers; three brothers), occurrence of prostate cancer in each of the maternal or paternal lineage, or two relatives affected before 55 years of age.

Analysis of patient presentation revealed that there was a significant difference in the age of the patient at presentation: HPC cases were diagnosed on average 2.9 years earlier than SPC. Furthermore, early onset prostate cancer (under 55 years) was observed more frequently in familial-associated PCa patients (13.4% of cases) compared to SPC (2.5% of cases). Patients with familial prostate cancer also appeared to present with a higher rate of locally advanced cancer than sporadic prostate cancer (38.2% vs 32.8%, respectively). Although there were no differences in PSA value at diagnosis between the HPC and SPC groups, there was a significant difference in histologic grading (p=0.023) with the lowest proportion of well-differentiated tumours (G1) in SPC patients.

With regard to clinical outcomes, no difference in prostate cancer specific mortality between the subgroups was calculated. However, analysis of biochemical recurrence-free survival showed that family history had a minor effect on disease outcomes following radical prostatectomy: pairwise comparison of HPC and SPC patients revealed a HR of 1.27 (p=0.002), with a marginal reduction in the 10-year biochemical recurrence free-survival rate for HPC patients (53.0%) compared to SPC patients (58.7%). Proportional hazard regression analysis also confirmed family history as a prognostic of biochemical recurrence-free survival.

Therefore, this data suggests that in a contemporary screening and treatment environment, a family history of prostate cancer may slightly increase the risk of PSA recurrence after radical prostatectomy, but with current management does not have a significant impact on risk prostate cancer-specific mortality.

The differences in patient presentation between the HPC and SPC subgroups could potentially be explained by increased awareness and health-seeking behavior in patients with a family history of prostate cancer. The differences in histologic grading between HPC and SPC is interesting; however, the dataset did not include information on mutation of high-risk genes or single-nucleotide polymorphisms related to prostate cancer aggressiveness and progression, and so further research is required to examine this observed link.

3: Prospective investigation of environmental risk factors for prostate cancer in the UK

The aetiology of prostate cancer is currently not very well understood, and whilst there are well-established risk factors - namely age, ethnicity and family history – these are non-modifiable. Although some of the variation will be attributed to differences in PSA testing programmes, that worldwide prostate cancer incidence rates show relatively high variation suggests that environmental factors may play a role in the development of prostate cancer.

The UK Biobank is a prospective study database, designed to be a resource for research into the causes of disease in middle and old age. A study published this month has utilised the database to analyse the data sets of 219,335 men between the ages of 40 and 69, to investigate the association between potential risk factors and prostate cancer.

Unsurprisingly, analysis showed that ethnicity was a significant risk factor for prostate cancer diagnosis: compared to men of white ethnicity, Asians had a lower risk (HR=0.62, 95% CI 0.47-0.83) and black men had a higher risk (HR=2.61, 2.10-2.34) of prostate cancer. Furthermore, men with any first-degree family history of prostate cancer (1.94, 1.77–2.13), and who reported that they had been diagnosed with an enlarged prostate (1.54, 1.38–1.71) had an elevated risk of prostate cancer. Men with a brother and father diagnosed with prostate cancer had an even high risk of diagnosis compared to men with no family history (3.35, 2.33–4.81).

No association between prostate cancer risk and deprivation, education, unemployment or living with a partner was found.

After multivariable adjustment, men living in London were significantly more likely to be diagnosed with prostate cancer than men living in North West England, North-East England, Yorkshire and the Humber and South-West England. However, it is possible that this can be at least partially explained by differences in the detection of asymptomatic prostate cancer.

A limitation of the study is that there is potential for detection bias. For example, obesity (BMI ≥30–<35 vs <25 kg m-2: HR = 0.88, 95% CI 0.81–0.97) and morbid obesity (BMI ≥35 vs <25 kg m-2: HR= 0.75, 0.64–0.88), were significantly inversely associated with prostate cancer risk. Moreover, current smokers (0.85, 0.77–0.95) and former smokers (0.93, 0.88–0.99) were reported to have a significantly lower risk of prostate cancer than non-smokers.

Men who had no children had a reduced prostate cancer risk (never vs ever, HR = 0.89, 95% CI 0.81–0.97), which has previously been reported. However, this may be resulting from increased health-seeking behaviour in men with children, as has previously been suggested. This could also explain the result that men who reported they had previously received a PSA test (1.31, 1.23–1.40) had an increased risk of prostate cancer than men who had not.

Men who reported they had never had sex (never vs ever, HR = 0.53, 0.33–0.84) also had a lower risk of prostate cancer, and no link between vasectomy and increased risk of prostate cancer was detected.

In summary, this study has highlighted the uniqueness and variety of data held by the UK Biobank, and has been able to suggest novel risk factors for prostate cancer as a result. However, some of the findings described here may be linked with health-seeking behaviour and detection bias rather than a true association with prostate cancer, which would need to be investigated further before concrete conclusions are made. 

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