Clinical implications of family history of prostate cancer and genetic risk single nucleotide polymorphism (SNP) profiles in an active surveillance cohort

摘要

Objectives class="unordered" style="list-style-type:disc" id="L1">To explore the potential prognostic role of family history (FH) of prostate cancer and prostate cancer risk single nucleotide polymorphisms (SNPs) in patients undergoing active surveillance (AS) for prostate cancer.This is the first study to date, which has investigated the potential prognostic role of SNP profiles in an AS cohortPatients and methods class="unordered" style="list-style-type:disc" id="L2">FH data were collected from patients in the Royal Marsden Hospital AS study.In all, 39 prostate cancer-risk SNPs identified from published genome wide association studies (GWAS) were genotyped using the Sequenom Platform and TaqMan^™ assays from available DNA.The cumulative genetic-risk scores for each patient were then calculated using the weighted effect estimated from previous GWAS (log-additive model).FH status and the genetic-risk scores were assessed against adverse outcomes in AS, time to treatment and adverse histology on repeat biopsy, using univariable and multivariable Cox regression models to address time to treatment; and binary logistic regression to address biopsy upgrade.Results class="unordered" style="list-style-type:disc" id="L3">Of 471 patients, 55 (13.6%) had adverse histology on repeat biopsies and 145 (30.8%) had deferred treatment.On univariate analysis, there was no significant relationship between FH of prostate cancer in any degree of relation, and adverse histology or time to treatment.For risk score analyses, 386 patients’ DNA was studied; and there was also no relationship found between the calculated genetic risk scores and adverse histology or time to treatment (P = 0.573 and P = 0.965, respectively).The retrospective study design and the few events was the main limitation of the study.Conclusions class="unordered" style="list-style-type:disc" id="L4">There is currently insufficient data to support the use of FH status or prostate cancer SNP profile-risk scores as prognostic factors in AS and these should not be used to influence management decisions.As more genetic variants are discovered this may change and should be reassessed in multicentre AS cohorts. class="kwd-title">Keywords: active surveillance, family history, genetic risk profiles, prostate cancer class="head no_bottom_margin" id="S1title">IntroductionProstate cancer is one of the most heritable cancers and a positive family history (FH) of prostate cancer increases risk to first-degree relatives by over two-fold []. Mutations that have moderate to high penetrance for prostate cancer, including BRCA2 and HOXB13, have been implicated in some families, but these rare variants are unlikely to explain the inherited genetic predisposition to prostate cancer in the vast majority of the population [, ]. The search for further causative genetic variants has led to genome-wide association studies (GWAS), which have so far identified 47 susceptibility loci associated with prostate cancer that occur more commonly but are of a lower penetrance. Following on from the discovery of these variants, efforts are now underway to evaluate their potential clinical application.Epidemiological studies have reported differences in outcomes amongst races in prostate cancer [], which persist despite correcting for socio-economic factors, e.g. access to healthcare and screening. Retrospective cohort studies have also shown familial aggregation of fatal prostate cancer cases []. These results suggest a potential role of inherited factors as prognostic markers for worse disease. However, the GWAS susceptibility loci have so far not been conclusively linked to disease aggressiveness and survival []. Their clinical utility as prognostic markers is therefore still undefined. The ability to predict disease aggressiveness or response to treatment, using inherited variables including FH and genetic variants would be invaluable, allowing clinicians to tailor treatment according to risks. A cohort where this might prove useful is in active surveillance (AS) cohorts where early identification of disease progression is vital.AS is an accepted management option for early prostate cancer. Several groups have reported results from AS programmes, which support its use []. For favourable-risk cancers, AS is seen as a potential option to avoid toxic therapies. The challenge is to identify disease progression to ensure prompt treatment before local advancement of the cancer or the development of distant metastases []. Men are monitored regularly with PSA testing and repeat biopsies to look for evidence of progression. However, there exists a certain subset of men, who have early disease progression and spread, despite their low-risk disease. Over the years, several advances have been reported that improve our ability to identify men early who are at risk of disease progression including, MRI scanning techniques and transperineal prostate biopsy mapping, which improves tumour sampling by reducing the random and systematic errors of TRUS-guided biopsy []. PSA kinetics as prognostic markers have also been investigated by different groups with conflicting outcomes [, ]. The Transatlantic Consensus Group’s recommendations, were published recently, which emphasised the need for further studies to define an optimal approach for AS with regard to determination of disease progression and trigger for active treatment []. The roles of genetic variants or FH as predictors for disease progression in this cohort have not been clearly defined. If patients with a positive FH or those with specific genetic profiles are at risk for worse outcomes, these men should potentially be discouraged from AS. Here, we report a study exploring the potential prognostic roles of FH or genetic-risk scores in patients managed by AS.