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Family History Can Determine the Patient's Disease Process Management Outcome

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Abstract

Background

The influence of family history on oncological outcomes of prostate cancer remains controversial. We conducted a systematic literature review and meta-analysis to investigate the impact of family history of localized prostate cancer on oncological outcomes.

Methods

On May 2020, we systematically searched MEDLINE, the Cochrane library, and Scopus for studies that compared patients who had localized prostate cancer with or without a positive family history of prostate cancer. Our aim was to evaluate the association of family history with biochemical recurrence-costless survival, cancer-specific survival, and overall survival past means of a multivariate Cox regression analysis.

Results

11 studies with 39,716 patients were included in the systematic review, and viii studies with 33,027 patients for the meta-assay. A positive family history was not associated with worse biochemical recurrence-costless survival (pooled HR: 0.96; 95% CI: 0.79–1.17) or cancer-specific survival (pooled HR: i.1; 95% CI: 0.52–ii.35). Subgroup analyses showed no association betwixt positive family history and poor biochemical recurrence-free survival in prostate cancer patients treated with radical prostatectomy (pooled Hour: 0.99; 95% CI: 0.76–i.31) or radiations therapy (pooled HR: 0.93; 95% CI: 0.67–1.30).

Conclusions

This meta-analysis indicated that family history of prostate cancer does non increase the adventure of biochemical recurrence or cancer-specific bloodshed in localized prostate cancer patients.

Introduction

Prostate cancer (PCa) is the second most frequent male cancer in worldwide [1], and a family history of PCa is a well-known risk factor for the development of this disease. The individual relative run a risk of a PCa diagnosis is doubled in offset-caste male relatives of PCa patients [2], and 10–20% of PCa patients are reported to have a positive family history among their offset-caste relatives [3]. Although numerous studies accept focused on the clinicopathological features associated with family history of PCa [4,5,6], clinical ascertainment has shown no substantial differences between PCa patients with family history and those without, except that family unit history is associated with younger age at diagnosis [ii]. Recent findings point to genetic factors that underlie familial aggregations of PCa; genetic differences betwixt patients with and without family unit history of PCa can be based on single-nucleotide polymorphisms or germline mutations, including HOXB13, BRCA1, BRCA2, and MLH1, which are associated with an increased risk of familial PCa [7,eight,9,10,11].

The influence of family history on oncological outcomes is less clear. For example, Kupelian et al. reported a negative clan between family history and survival outcomes [12], while Westerman et al. stated that family history of PCa was significantly correlated with improved oncological outcomes [13]. Clearly, further piece of work is needed to fully understand the prognostic value of family history in oncological outcomes for patients with localized PCa. Such an understanding could contribute to improved clinical practices and facilitate the procedure of shared determination-making with patients.

Therefore, in this written report, we hypothesized that the family history would influence the oncological outcomes in localized PCa. To verify this hypothesis, we conducted a systematic review and meta-assay of the literature to investigate and summarize the association between family history and oncological outcomes in localized PCa.

Material and methods

Literature search strategy

Nosotros performed this systematic review and meta-assay according to the Preferred Reporting Items for Systematic Reviews and Meta-assay statement [xiv]. The protocol was preregistered in the International Prospective Register of Systematic Reviews database (PROSPERO: CRD42020188782). We searched MEDLINE, Cochrane Library, and Scopus databases on May 11, 2020 for studies published through Apr 2020 investigating the impact of family history on oncologic outcomes in localized PCa patients. To expand the data search, nosotros attempted to identify unpublished studies in ISRCTN registry ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, OpenGrey, and Database of Abstracts of Reviews of Furnishings on the same solar day. The commencement screening was based on study title and abstract, after which the full-text papers were assessed for eligibility. All extracted data were crosschecked to ensure their appropriateness based on total-text review. Two authors (FU and SK) independently carried out this process, and all discrepancies were mostly resolved by consensus or by referring to the senior author (SE). The following string terms were used in this study: "prostate cancer" and "family history", and "biochemical recurrence" OR "oncological outcome" OR "overall survival". Biochemical recurrence-free survival (BCRFS) was our primary outcome of interest, and cancer-specific survival (CSS), and overall survival (OS) were secondary outcomes. EndNote X8 was used equally a bibliography management software.

Pick criteria

Studies were considered eligible if they compared localized PCa patients (patients) with a positive family history (exposure) to those without family history (comparison) to assess the effect of family unit history on BCRFS, CSS, and Bone (outcomes), utilizing univariate and multivariable Cox regression analysis in accomplice studies. Articles published in languages other than English, reviews, commentaries, instance series were excluded. If there were multiple manufactures published past aforementioned group using similar cohorts, either the more contempo or the higher quality publication was included.

Data extraction

2 authors (FU and SK) independently extracted data from all the eligible studies. The following characteristics were contained: first author's name, publication year, country in which patients were enrolled, recruitment period, number of patients, age, prostate-specific antigen (PSA), primary therapy, follow-upward duration, and family history of PCa. Hazard ratios (HRs) and 95% conviction intervals were determined for family history of PCa associated with each of the oncological outcomes. All discrepancies regarding information extraction were generally resolved by consensus or by a meeting with the other authors (SY, KT, TK, and SE).

Statistical assay

A forest plot was used to assess HRs from the multivariable analyses of private studies and obtained a summary Hr for the effect of family history in localized PCa on cancer progression and mortality. Studies with general logistic regression, log-rank, Kaplan–Meier, univariable Cox proportional hazard regression analyses were not included in this meta-analysis. In cases where simply the 60 minutes and P value were reported, we calculated the 95% CI [xv, sixteen]. Statistical heterogeneity among the studies was assessed using the Cochrane Q test and I-square examination. P value < 0.05 in the Cochrane Q test and a ratio >l% in the I-square examination were defined as statistically significant. The summary HRs, and the 95% CI were calculated using random effects models. Fixed effect models were used to calculate pooled HRs for not-heterogeneous results [17,18,nineteen]. Publication bias was determined using funnel plots. The level of statistical significance was set at P values < 0.05. Statistical analyses were all conducted using the Stata/MP, version 14.2 (Stata Corp., Higher Station, TX, USA)

Quality assessment

We assessed the quality of included studies using The Newcastle-Ottawa Calibration [20] based on the Cochrane Handbook for systematic reviews [21, 22]. The scale is allocated according to iii domains: population selection (maximum of iv stars), comparability of the group (maximum of two stars), and ascertainment of exposure (maximum of three stars). The total scale ranges from 0 to 9. The main confounders were identified as the of import prognosis factors of BCRFS, CSS, and Bone. The presence of confounders was adamant by a review of reported data and consensus. Nosotros identified those studies with scores higher than 6 every bit "high-quality" choices.

Risk of bias

We assessed the run a risk-of-bias of the included studies according to the Cochrane Handbook for Systematic Reviews of Interventions for including non-randomized studies [22]. The confounding factors were selected as the about common prognostic factors at the time of diagnosis. The articles were therefore reviewed based on the aligning for the issue of age, PSA, tumor staging, and grading according to the investigated outcomes. The Chance Of Bias In Not-randomized Studies of Interventions tool was used for BCRFS and CSS analyzed [23]. The run a risk of bias of each study was assessed by two authors (FU and SK), independently. Discrepancies were resolved past consultation with the senior author (SE). The results of risk-of-bias assessment were summarized in Supplementary Tables (Tables S1, S2).

Results

Study selection

Overall, 316 articles were identified from the search query, of which 232 articles were removed after title and abstract assessment (Fig. i). No unpublished study was identified by Gray Literature search. An additional 73 manufactures were excluded later on full-text evaluation. Finally, the remaining 11 articles were included in the systematic review [6, xiii, 24,25,26,27,28,29,xxx,31,32] and 8 articles in the qualitative meta-analysis [xiii, 25,26,27,28, xxx,31,32].

Fig. 1: Written report selection process.
figure 1

Menses nautical chart for the process of article selection to analyze the impact of family unit history on oncological outcomes.

Total size image

Written report population

The studies' characteristics and patients' clinical information are summarized in Tables ane, 2, respectively. The xi studies incorporate 39,716 treatment-naive PCa patients. The examined populations were Northern American in ix studies, European in one, and Asian in one. All studies were published betwixt 1999 and 2017. The definition of family history was the presence of one or more get-go-caste relatives in ten studies; the strict definition including hereditary PCa and sporadic PCa was used in the remaining study. The number of patients with family history was provided in all 11 studies and deemed for 10,471 of all 39,716 patients (26.4%). Median or mean follow-up ranged from 40 months to 9.9 years. In well-nigh studies, the median or mean age of patients with family unit history was younger than in those without. The value of median or hateful PSA was similar between PCa patients with and without family history. Primary therapies were radical prostatectomy (RP) or radiation therapy (RT). But a univariate Cox regression assay was performed in 3 studies, which were excluded from meta-analysis. A multivariate Cox regression analysis was applied to the remaining eight studies. Meta-analyses were conducted for BCRFS and CSS. Only ii studies evaluated the association of Bone with family history: Westerman et al. reported the rate of 10-year Bone was greater in patients with family unit history than in those without, only Bagshaw et al. constitute no significant difference in OS betwixt patients with or without family history [13, 31].

Tabular array one The studies' characteristics of all included articles.

Full size table

Table two The patients' clinical data in all included articles.

Full size tabular array

Meta-analysis

Association betwixt family history and biochemical recurrence-gratuitous survival

Eight studies including 33,027 patients provided data on the association of family history with biochemical recurrence (BCR). All patients had localized PCa and were treated with RP or RT. The forest plot (Fig. 2A) revealed that family unit history of PCa was not associated with BCR in localized PCa patients (pooled Hour, 0.96; 95% CI, 0.79–one.17; z = 0.39). The Cochrane Q test (c two = 18.02; P = 0.012) and I-square test (I ii = 61.ii%) showed significant heterogeneity. The funnel identified one study over the pseudo 95% CI (Fig. 2A).

Fig. 2: Forest and funnel plots showing the association of family history with oncological outcomes in localized prostate cancer patients.
figure 2

A Biochemical recurrence-gratis survival; B cancer-specific survival.

Total size paradigm

Association between family history and cancer-specific survival

3 studies including 28,506 patients provided information on the association of family history with cancer-specific bloodshed (CSM). The forest plot (Fig. 2B) showed that family history of PCa was not associated with CSS in localized PCa patients (pooled HR, 1.i; 95% CI, 0.52–2.35; z = 0.26). The Cochrane Q examination (c 2 = 11.74%; P = 0.003) and I-square test (I 2 = 83.0%) showed significant heterogeneity. The funnel plot identified one study over the pseudo 95% CI (Fig. 2B).

Subgroup analysis

Association betwixt family history and BCRFS of prostatectomy

Iv studies including 29,043 patients provided data on the association of family history with BCR of RP. All patients had localized PCa and were treated with RP. The forest plot (Fig. S1A) revealed that family history of PCa was non associated with BCRFS in localized PCa patients treated with RP (pooled Hour, 0.99; 95% CI, 0.76–1.31; z = 0.04). The Cochrane Q examination (c ii = xiv.18; P = 0.007) and I-square test (I 2 = 71.8%) showed significant heterogeneity. The funnel plot identified i written report over the pseudo 95% CI (Fig. S1A).

Association betwixt family history and BCRFS after radiation therapy

Iii studies including 3984 patients provided information on the clan of family history with BCR after RT. All patients had localized PCa and were treated with RT. The forest plot (Fig. S1B) revealed that family history of PCa was non associated with BCRFS in localized PCa patients treated with RT (pooled HR, 0.93; 95% CI, 0.67–ane.30; z = 0.43). The Cochrane Q test (c two = 3.46; P = 0.178) and I-square test (I 2 = 42.ane%) showed no significant heterogeneity. The funnel plot did not identify whatsoever publication bias (Fig. S1B).

Discussion

To the best of our knowledge, our written report is the first systematic review and meta-analysis investigating the touch on of family unit history on oncological outcomes in localized PCa. In meta-assay, nosotros assessed data from eight published articles with a combined patient population of more than 33,000 patients. As simply two studies evaluated the association of OS with family history, we excluded OS from the oncological outcomes in this meta-analysis. Nosotros plant that family history of PCa did not increase the adventure of BCR and CSM. In an additional sub-analysis, we evaluated the association of family unit history with BCR in patients treated by RP and RT, respectively, and institute the aforementioned results equally from the main analysis.

Although based on retrospective analyses with relatively small number of samples, some early on reports suggested that patients with family history of PCa may experience more aggressive features of the disease [12, 33, 34]. Nonetheless, our meta-analysis showed that oncological outcomes for patients with PCa did not differ substantially in the presence or absenteeism of family unit history.

The clinical application of PSA screening is idea to be ane of the main reasons for inconsistencies in these results. PSA screening was approved past the United States Food and Drug Administration in 1986 as a test to monitor patients with PCa, and in 1994 it was approved every bit a screening aid for diagnostic detection [35]. Some reports suggest that family history of PCa was an independent risk factor for aggressive oncological outcome in cohorts that did not receive PSA screening or that were studied earlier such screening became widely available, and that family history presented more favorable affliction outcomes in PSA-screened cohorts [29, 36]. In addition, Lee et al. reported that, after the introduction of PSA testing, the risk of PCa diagnosis was significantly increased by a PCa diagnosis in a brother [37]. Because PCa develops relatively slowly, men with a positive family history of PCa are more likely to pay attending to their wellness and thus have a higher chance of detecting PCa in its early on stages through PSA screening, which in turn produces a somewhat protective effect of family unit history. Indeed, family history is reported to be associated with a college likelihood of PCa diagnosis at a younger age [ii]; in our systematic review, the historic period of diagnosis was lower in PCa patients with a positive family unit history than in those without (Table 2).

On the other manus, Spangler et al. reported that family history of PCa was associated with higher tumor stage at diagnosis in men diagnosed before threescore years of age, and that men over 60 who had family unit history of PCa were significantly more likely to experience BCR [27]. Whether younger diagnostic age is related to earlier presentation for diagnosis because of increased familial awareness of the disease or whether the earlier age at diagnosis reflects a biological characteristic of familial PCa remains uncertain. However, with the availability of PSA screening, although the relative risk for PCa diagnosis doubled in start-degree male relatives of PCa patients [2], family history of PCa did not increase the risk of worse oncological effect for PCa. These results point that PCa patients with a positive family unit history need non worry excessively virtually their oncological outcome if they receive regular PSA screening.

Although the present study represents the first systematic review and meta-analysis that evaluated the effects of family history of PCa on oncological outcomes, in that location are several limitations. In this report, articles published in other than English were excluded, increasing the risk of option bias. Just non-randomized observational studies were included and all of them had a retrospective design. The studies differ in their methods for collecting family history data, with several studies relying on patient self-reporting and dr. queries to make up one's mind the presence or absence of family history of PCa, increasing the risk of recall bias. In addition, although at the time of this writing the primary handling options for localized PCa were RP, RT, androgen deprivation therapy, and active surveillance, just RP and RT were selected for our meta-assay. The definition of family unit history is also a limitation. In most of the studies, the definition of family unit history was one or more first-caste relatives, but several contempo reports discuss hereditary PCa, which suggests subgroups of familial PCa with a likelihood of genetic predisposition [iii, 32, 38]. Few studies accept assessed this item patient group, and the evaluation of the risk of hereditary PCa may provide different results. The heterogeneity of germline genetic mutations in PCa was non besides evaluated in this written report. Further investigation will exist required to elucidate the bear on of these subtypes on oncological outcomes of PCa.

Conclusion

This study is the first systematic review and meta-assay investigating the touch of family history on oncological outcomes in localized PCa. Although several limitations were included, the results of this meta-analysis suggest that family unit history of PCa did non increase the risk of BCR or CSM in localized PCa patients. These results will be utilized for patient counseling.

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  1. Department of Urology, The Jikei Academy School of Medicine, Tokyo, Nippon

    Fumihiko Urabe, Shoji Kimura, Shutaro Yamamoto, Kojiro Tashiro, Takahiro Kimura & Shin Egawa

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Urabe, F., Kimura, S., Yamamoto, South. et al. Impact of family unit history on oncological outcomes in master therapy for localized prostate cancer patients: a systematic review and meta-assay. Prostate Cancer Prostatic Dis 24, 638–646 (2021). https://doi.org/10.1038/s41391-021-00329-0

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