Cancer Causes Control DOI 10.1007/s10552-014-0364-8

ORIGINAL PAPER

Coffee consumption and prostate cancer risk: an updated meta-analysis Yu Lu • Limin Zhai • Jie Zeng • Qiliu Peng • Jian Wang • Yan Deng • Li Xie • Cuiju Mo • Shi Yang • Shan Li • Xue Qin

Received: 28 July 2013 / Accepted: 19 February 2014 Ó Springer International Publishing Switzerland 2014

Abstract Purpose Many epidemiological studies have been conducted to explore the association between coffee consumption and prostate cancer. However, the results remain inconsistent. We performed a large meta-analysis of relevant studies to derive a more precise estimation of this relationship. Methods Systematic searches of PubMed and several other databases up to June 2013 were retrieved. All epidemiologic studies regarding coffee consumption and prostate cancer risk were included, and odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the strength of the association. Results Twelve case–control studies involving 7,909 prostate cancer cases and 9,461 controls and nine cohort studies involving 455,123 subjects were included in our analysis. Compared with the lowest category, the unstratified highest category of coffee consumption showed a Yu Lu, Limin Zhai, and Jie Zeng have contributed equally to this work and should be considered as co-first authors.

Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0364-8) contains supplementary material, which is available to authorized users. Y. Lu
L. Zhai
Q. Peng
J. Wang
Y. Deng
L. Xie
C. Mo
S. Yang
S. Li (&)
X. Qin (&) Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China e-mail: [email protected] X. Qin e-mail: [email protected] J. Zeng Department of Clinical Laboratory, Liuzhou City People’s Hospital, Liuzhou, Guangxi Zhuang Autonomous Region, China

significance reduction in prostate cancer risk of a fixedeffects model (OR 0.91, CI 0.86–0.97). A borderline significant influence was also found when the stratified highest category (US C4, Europe C5) of coffee consumption was compared with the reference category (OR 0.96, CI 0.92–1.00), but no relationships were observed for the other two categories. In another analysis conducted by coffee consumption and prostate cancer stage and Gleason grade, our results showed a significant inverse association in all categories of prostate cancer except Gleason \7 grade in a fixed-effects model; the results remained the same, except for advanced prostate cancer, in a random-effects model. Conclusions Our meta-analysis suggests that high (e.g., highest C4 or 5 cups/day) coffee consumption may not only be associated with a reduced risk of overall prostate cancer, but also inversely associated with fatal and highgrade prostate cancer. Keywords Coffee consumption
Prostate cancer
Tumor stage
Tumor grade
Meta-analysis

Introduction Prostate cancer is the second most commonly diagnosed cancer, with almost one million new cases each year; and it is the sixth leading cause of cancer death among men [1]. Its incidence rates vary by more than 25-fold worldwide but with less variation in mortality rates (tenfold) [2], mainly because the wide utilization of prostate specific antigen (PSA) testing, and it has a much greater effect on incidence than on mortality. Further, the proportion of advanced-stage cancers has been reported much lower after PSA screening began [3]. However, due to the heterogeneous nature of prostate cancers (ranging from innocuous

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to aggressive), its etiology remains inconsistent; various risk factors may be responsible for the development of different subgroups of prostate cancer. According to the Health Professionals Follow-Up Study conducted by Giovannucci et al. [3], for instance, in incident and fatal prostate cancer, four factors including African-American race, positive family history, higher tomato sauce intake (inversely), and a-linolenic acid intake were statistically associated with overall incident prostate cancer, whereas six different factors such as recent smoking history, taller height, higher BMI were positively associated with fatal prostate cancer. And in advanced and non-advanced-stage prostate cancer, high tomato sauce intake was inversely associated with advanced prostate cancer. These results indicating that the risk and progression of prostate cancer may be linked to various environmental factors, especially dietary factors. Coffee, one of the most widely consumed beverages in the world, may be crucial in the etiology of prostate cancer [4]. Coffee has been reported to contain more than a thousand different chemicals [5], several of which potentially impact the etiology of diseases ranging from carcinogenesis to cellular apoptosis [6, 7]. Since the 1960s, the possible relationship between coffee consumption and prostate cancer risk has been investigated in epidemiological studies [8]; however, the results have been inconsistent. An earlier metaanalysis regarding coffee consumption and risk of prostate cancer, conducted by Park et al. in 2010 [9], reported a significant positive (harmful) association in seven case– control studies, but a null association in four cohort studies. Another meta-analysis, conducted on cohort studies in 2011 [10], showed that coffee drinking was associated with a reduced risk of prostate cancer. Both of the meta-analyses were methodologically flawed, as they compared only the lowest and highest intakes. Since the meta-analysis, five large, prospective, cohort studies [11–15] and four case– control [16–19] studies have been conducted to estimate the association between coffee consumption and prostate cancer risk. To provide an updated result on this topic and derive a more precise estimation of this relationship, in the present study, we systematically performed a review and metaanalysis to assess quantitatively the association between coffee consumption and prostate cancer risk.

Methods

comprehensive literature search of PubMed, Embase, the Cochrane Library, and the China National Knowledge Infrastructure covering all papers published up to June 2013 was conducted, using the keywords ‘‘coffee,’’ ‘‘caffeine,’’ ‘‘beverages,’’ ‘‘diet,’’ ‘‘drinking,’’ and ‘‘lifestyle,’’ all combined with the Medical Subject Heading (MeSH) term ‘‘Prostatic Neoplasms.’’ Language restrictions were not used, and the reference lists of relevant articles were checked manually to find additional eligible studies. Inclusion and exclusion criteria The inclusion criteria were as follows: (1) case–control or cohort study; (2) evaluation of the association between coffee consumption and the risk of prostate cancer; (3) relative risks (RRs) estimate, odds ratios (ORs), or hazard ratios (HRs) provided with the corresponding confidence interval (CI) of prostate cancer relating to every category of coffee intake; and (4) frequency of coffee consumption reported. Exclusion criteria included (1) reviews, metaanalyses, letters, and comments and (2) articles without sufficient information for data extraction. When duplicate reports from the same study cohort were identified, we chose the most recent or largest population. Data extraction Data from each paper fulfilling the inclusion criteria were extracted carefully by two independent reviewers (Y. L. and X. Q.). The data extracted included first author, year of publication, country of origin, study design (case–control or cohort study), type of case–control study (hospital- or population-based study), follow-up period, number of cases and controls (participants for cohort studies), coffee consumption rate, adjustment for potential confounders, prostate cancer stage and Gleason grade, and the RRs or ORs or HRs together with their 95 % CIs for every category of coffee intake. If coffee consumption was indicated by different measurements in the original studies, we defined 240 mL or 8 oz of coffee as equal to one cup. In addition, the OR was assumed to be the same as the RR and HR, due to the low incidence of prostate cancer, and the summary results are reported as OR for simplicity [22]. Finally, if different results were generated, disagreement was resolved through discussion between the two authors. If the authors could not reach an agreement, a third reviewer (S. L.) was consulted.

Literature search Quality score assessment This study was performed according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting [20] and the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement [21]. A

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The methodological quality of the eligible studies included in our meta-analysis was independently assessed by two reviewers (L. Z. and J. Z.) according to the nine-star

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Newcastle–Ottawa Scale (NOS) [23]. In the NOS, the score ranges from 0 to 9 stars. Because no standard criteria have been established for a high-quality study, we considered a case–control study score C6 stars and a cohort study score C8 stars to be high quality in the present study. Statistical analysis Summary ORs and corresponding 95 % CIs of the included studies were used as a measure to assess the association of coffee consumption with prostate cancer risk. Meta-analyses for different levels of consumption were conducted separately. As in a previous meta-analysis of coffee intake [24], we distinguished four levels of coffee consumption: (1) the highest category of coffee consumption (US studies, C4 cups/day; European studies, C5 cups/day); (2) the second highest category (US studies, 2–3 or C2 cups/day; European studies, 3–4 or C3 cups/day); (3) the third highest category (US studies, B1 cup/day; European studies, 1–2 cups/day); and (4) the reference category (US studies, 0 cup/day; European studies, \1 cup/day); and the unstratified highest category of coffee consumption was defined as the highest level of coffee consumption in each included study. We also conducted another analysis regarding coffee consumption and prostate cancer stage and Gleason grade. A subgroup analysis, stratified by study design, study region, and quality of study, was summarized. The Q test and I2 statistics were used to assess the statistical heterogeneity among studies. If a statistical difference in heterogeneity existed (p \ 0.10 or I2 C 50 %), a random-effects model (the DerSimonian and Laird method) was selected to pool the data; otherwise, a fixed-effects model (the Mantel–Haenszel method) was used. Sensitivity analysis was performed to identify potentially influential studies, both in the overall pooled estimate and within the subgroups. To examine possible publication bias, funnel plots and the Egger regression asymmetry test were used (p \ 0.05 was considered a significant publication bias). All statistical analyses were performed using STATA software version 11.0 (Stata Corp, College Station, TX), and all p values were two-sided.

Results Study characteristics As shown in Fig. 1, a total of 181 studies were identified. After excluding 132 irrelevant titles and/or abstracts, the remaining 49 full-text articles were reviewed for more detailed evaluation. Of those articles, 28 were excluded as irrelevant and 21 studies relevant to the role of coffee consumption and the risk of prostate cancer were included in our meta-analysis [11–19, 25–36]. Of the selected studies, 12

were case–control studies, including 7,909 cases and 9,461 controls, and nine were cohort studies with a total of 455,123 subjects (33,473 cases). Of the 21 studies, six were conducted in the USA, seven in Europe (three in Sweden, two in Italy, one in the UK, and one in Greece), five in Canada, and three in Asia (one each in India, Taiwan, and Japan). Three studies only adjusted for age, while the other 19 studies adjusted for a wide range of potential confounders of prostate cancer, such as age, body mass index, smoking, alcohol, family history of prostate cancer, history of prostate cancer screening, geographic area, education, intake of calcium, intake of zinc, and diabetes. Eight of the case–control studies were population based, and four were hospital based. All studies included met quality criteria ranging from five to eight stars (See supplement Table S1). Detailed characteristics of the case–control studies and cohort studies included in this meta-analysis are presented in Table 1. Meta-analysis results The pool ORs (95 % CI) of prostate cancer for all studies combined were 0.91 (0.86–0.97) for the unstratified highest category of coffee consumption compared with the lowest category and 0.96 (0.92–1.00), 0.99 (0.95–1.04), and 0.99 (0.95–1.03) for the stratified highest, second highest, and third highest categories, respectively, compared with the reference category. A significant protective relationship between the unstratified highest category of coffee consumption and prostate cancer risk was observed, and a borderline significant influence was found in the stratified highest category. Similarly, significant results were also found in the unstratified and stratified highest categories in subgroup analyses conducted by study design in cohort studies (OR 0.89, 95 % CI 0.84–0.95 and OR 0.96, 95 % CI 0.92–1.00, respectively) and by study region in USA studies (ORs 0.93, 95 % CI 0.87–0.99 and ORs 0.96, 95 % CI 0.92–1.00, respectively). To a larger extent, a significantly decreased prostate cancer risk was found in subgroup analysis in Europe studies (ORs 0.87, 95 % CI 0.78–0.97) and high-quality studies (ORs 0.91, 95 % CI 0.85–0.97) when the analysis was restricted to unstratified highest category of coffee consumption. However, no significant association was noted in the other categories and their subgroup analyses. Details are presented in Table 2. In another analysis conducted according to coffee consumption and prostate cancer stage and Gleason grade, the former were classified into localized (defined as cancer confined to within the prostate), advanced (defined as death or stage T3–T4, N1, or M1 at diagnosis), and fatal (defined as death from prostate cancer) prostate cancer based on the majority studies included [11, 13–15, 17]. The latter were categorized as high grade (Gleason sum at diagnosis 7–10) or low grade (Gleason sum 2–6). Because only six studies

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Cancer Causes Control Fig. 1 Flow chart showing study selection procedure

181

articles

identified

from

literature search

132 studies excluded on screening of titles and/or abstracts 49

potentially

relevant

papers

identified for full-text review 28 studies excluded after full-text review: 8 review or meta-analysis 7 lack of RRs (or ORs) or corresponding 95% CI 2 letter or comment 1 duplicated data

10 not relevant studies 21

articles

included

in

this

meta-analysis

12 Case-control studies

provided the prostate cancer stage (two were case–control studies and four were cohort studies) and six reported the Gleason grade (four were case–control studies and two were cohort studies) (detail characteristic are presented in supplement Table S2), the pool ORs (95 % CI) of prostate cancer for the six included studies were restricted to the unstratified highest category (compared with the lowest category). Our results showed a significant inverse association in all categories of prostate cancer except the Gleason \7 grade: (1) localized (ORs 0.89, 95 % CI 0.83–0.96); (2) advanced (ORs 0.82, 95 % CI 0.69–0.96); (3) fatal (ORs 0.64, 95 % CI 0.47–0.80); (4) Gleason 7–10 (ORs 0.66, 95 % CI 0.51–0.81), (5) Gleason \7 (ORs 1.06, 95 % CI 0.86–1.25), using a fixed-effects model. As significant heterogeneity existed, a random-effects model was also used; the results remained the same, except for advanced prostate cancer (ORs 0.85, 95 % CI 0.58–1.12) (Table 3). Heterogeneity analysis There was no statistical significant heterogeneity in any of the stratified models in the overall studies. However, significant heterogeneity was observed in subgroup analysis, which included the cohort studies and high-quality studies in the second highest category of coffee intake (I2 = 52.7 %, I2 = 51.4 %, respectively), and Asian studies in the unstratified highest category of coffee intake (I2 = 64.2 %) (Fig. 2). However, the pool ORs remained

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9 Cohort studies

insignificant, and heterogeneity was not altered when the random-effects model was performed (data not shown). Sensitivity analysis A sensitivity analysis, in which individual studies were sequentially omitted, was performed to evaluate the stability of the results. The results demonstrated that the study by Bosire et al. [11] apparently influenced the overall results and the results for advanced prostate cancer. After excluding this study from the analysis, the pool ORs (95 % CI) of prostate cancer for overall studies remain significant in the stratified and unstratified highest coffee intake categories (OR 0.89, 95 % CI 0.82–0.96; OR 0.91, CI 0.83–0.99, respectively), and still insignificant in the second highest and third highest categories (OR 0.95, CI 0.80–1.09; OR 0.93, CI 0.85–1.01, respectively). In addition, no significant heterogeneity was observed in the four groups (I2 = 10.3 %, I2 = 16.8 %, I2 = 0.0 %, I2 = 25.9 %, respectively). Furthermore, a forest plot omitting Bosire’s study was conducted for advanced prostate cancer, and the result showed that the pool ORs became significant (OR 0.70, CI 0.55–0.86) and there was no evidence of heterogeneity (I2 = 46.5 %). Publication bias Begg’s funnel plots and Egger’s tests were performed to assess publication bias. As showed in Fig. 3, the shape of

USA, P-B

Sweden, P-B

Italian, P-B

India, H-B

USA, P-B

Sweden, P-B

Canada, P-B

Wilson et al. [17]

Polesel et al. [18]

Ganesh et al. [19]

Slattery and West [35]

Gronberg et al. [27]

Jain et al. [25]

Country, design

Geybels et al. [16]

Case–control studies (n = 12)

References

1989–1993

1959–1989

1983–1986

1999–2001

1991–2002

2001–2002

2002–2005

Study period

Coffee consumption categories

C4 cups/day

1.06 (0.69–1.62) 0.97 (0.60–1.57)

4–5 cups/day [5 cups/day

617/637

406/1,218

362/685

123/167

[500 g/day

0.97 (0.65–1.44)

0.84 (0.58–1.22)

1.91 (0.73–5.30)

6–9 cups/day

1.00

1.99 (0.78–5.46)

3–5 cups/day

0–500 g/day

1.77 (0.65–5.09)

1–2 cups/day

None

1.00

1.09 (0.75–1.60)

[20 cups/week None

1.00 0.99 (0.68–1.47)

None

1.3 (0.6–2.7)

1–20 cups/week

1.00

C5 cups/day Yes

1.11 (0.86–1.43) 1.05 (0.70–1.58)

3–4 cups/day No

1.05 (0.83–1.32)

1–2 cups/day

1.00

0.98 (0.65–1.49)

2–4 cups/day

1,294/1,451 \1 cup/day

0.97 (0.62–1.52)

1–2 cups/day

1.00

1.16 (0.90–1.50) 1.16 (0.82–1.63)

2–3 cups/day 1,489/1,112 \1 cup/day

1.22 (0.88–1.69) 1.13 (0.84–1.51)

1 cups/day

1.00

Adjusted OR or RR (95 % CI)

2–6 cups/week

894/860 \1 cup/week

Case/control

Table 1 Characteristics of the studies included in the final analysis (n = 21)

Age and total energy intake

Specific food items, smoking habits, and alcohol consumption

Age

Age, religion, and education

Center, age, education, occupational physical activity, family history of prostate cancer, diabetes, smoking habits, drinking, habits, nonalcohol energy intake, body mass index, body mass index at age 30 years

Age, region, smoking, BMI, education, intake of calcium, zinc, and total energy

Age, race, first-degree family history of prostate cancer, smoking status, and history of prostate cancer screening

Adjustment

6

6

5

7

6

5

5

Study quality

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123

123

Greece, H-B

Canada, P–B

Taiwan, H-B

Italy, H-B

Hsieh et al. [26]

Sharpe and Siemiatycki [32]

Chen et al. [29]

Gallus et al. [28]

USA

UK

Bosire et al. [11]

Shafique et al. [12]

Cohort studies (n = 9)

Canada, P-B

Country, design

Villeneuve et al. [36]

References

Table 1 continued

1970–2007

1995–2007

1991–2002

1996–1998

1979–1985

1994–1997

1994–1997

Study period

318/6,017

23,335/288,381

219/431

237/481

399/476

246/320

1,623/1,623

Case/control

0.95 (0.72–1.24) 0.93 (0.66–1.31)

0.94 (0.87–1.02)

C6 cups/day

C3 cups/day

1.00 (0.95–1.05) 1.00 (0.94–1.06)

2–3 cups/day 4–5 cups/day

1–2 cups/day

1.00 (0.95–1.06)

1 cup/day

1.00

1.03 (0.98–1.08)

\1 cup/day

None

1.00

1.9 (1.2–3.0)

3rd tertile None

1.00

1st tertile

1.00 1.88 (1.07–3.30)

1.1 (0.6–1.9) 0.9 (0.5–1.7)

3–4 drank/day C5 drank/day Non-drinkers

1.1 (0.6–1.9)

1–2 drank/day

Drinkers

1.00

None

1.15 (0.53–2.47)

C3 cups/day

1.1 (0.8–1.5)

C4 cups/day 1.00

1–3 cups/day None

0.8 (0.6–1.1) 1.0 (0.7–1.3)

\1 cup/day

1.00

Adjusted OR or RR (95 % CI)

None

Coffee consumption categories

Age at screening, cholesterol, systolic blood pres sure, BMI, alcohol intake, tea consumption, smoking status, social class

Age, race, height, BMI, physical activity, history of diabetes, family history of prostate cancer, PSA testing, intakes of tomato sauce, alpha-linolenic acid, and total energy intake

Age, study entry, education, occupational physical, activity at 30–39, BMI, and family history, and total energy intake

Age and BMI

Age, ethnicity, respondent, status, family income, BMI, cumulative cigarette, smoking, and cumulative, alcohol consumption

Age, height, BMI, and years of schooling.

Age, province of residence, race, years since quitting, smoking, cigarette pack-years, grains and cereals, alcohol, fruit and fruit juices, tofu, meat, income, and family history of cancer

Adjustment

7

8

5

6

5

5

6

Study quality

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Japan

USA

Swedish

USA

Canada

USA

Wilson et al. [14]

Discacciati et al. [13]

Hsing et al. [34]

Ellison [31]

Severson et al. [33]

Country, design

Li et al. [15]

References

Table 1 continued

1965–1986

1969–1993

1966–1986

1998–2010

1986–2006

1995–2005

Study period

0.74 (0.54–1.01) 0.63 (0.39–1.00)

1–2 cups/day C3 cups/day

C6 cups/day

0.94 (0.86–1.02) 0.83 (0.72–0.94)

1–3 cups/day 4–5 cups/day C6 cups/day

174/7,999

145/3,400

0.96 (0.39–2.37) 0.92 (0.59–1.44)

C5 cups/day

1.42 (0.77–2.61)

[750 mL/day

1.00

1.35 (0.75–2.43)

[500–750 mL/day

2–4 cups/week

1.42 (0.80–2.52)

[250–500 mL/day

B1 cup/week

1.00 1.14 (0.66–1.97)

None

1.0 (0.6–1.6)

C5 cups/day [0–250 mL/day

0.8 (0.6–1.2)

3–4 cups/day

1.00

1.01 (0.90–1.13) 1.00

\1 cup/day

1.09 (0.92–1.27)

0.82 (0.68–0.98)

1–3 cups/day 4–5 cups/day None

0.94 (0.85–1.05) 0.94 (0.86–1.04) 0.93 (0.83–1.04)

\1 cup/day

1.00

0.82 (0.62–1.08)

Occasionally

None

1.00

Adjusted OR or RR (95 % CI)

None

Coffee consumption categories

149/17,633 \3 cups/day

3,801/44,613

5,035/47,911

318/18,853

Case/control

Age

5-year age group and wine consumption

Age

Tea, alcohol, BMI, personal history of diabetes, family history of prostate cancer, family history of prostate cancer, physical activity, education, total energy intake

Race, height, BMI at age 21, current BMI, vigorous physical activity, smoking, diabetes, family history of prostate cancer in father or brother, multivitamin use, intakes of processed meat, tomato sauce, calcium, alpha-linolenic acid, supplemental vitamin E, alcohol intake, energy intake, history of PSA testing

Age, education level, BMI, time engaging in sports or exercise, marital status, time spent walking, smoking status, family history of cancer, consumption of tea

Adjustment

8

7

6

8

6

8

Study quality

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the funnel plot did not reveal any evidence of obvious asymmetry. However, the Egger’s test, which provides statistical evidence of funnel plot symmetry, suggested a significant publication bias in the unstratified highest category (p = 0.020, data shown in the funnel plot). No publication bias was found in the other groups.

8

Study quality

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123

4Q; 1.1 (0.7–1.7)

3Q; 1.2 (0.8–1.8)

2Q; 0.9 (0.6–1.4)

Age, ethnicity, and income 1Q; 1.0 2Q and 3Q ranges for the variables were as follows: coffee 0–2.5 cups/day 198/20,316 1975–1980 USA Le Marchand et al. [30]

References

Table 1 continued

Country, design

Study period

Case/control

Coffee consumption categories

Adjusted OR or RR (95 % CI)

Adjustment

Discussion In our meta-analysis, a significant protective relationship between the unstratified highest category of coffee consumption and prostate cancer risk was observed. A borderline significant influence was also found in the stratified highest category. Participants who drank more than 4–5 cups of coffee per day had a 3–14 % lower risk of prostate cancer compared with those who did not drink coffee or who drank less than one cup per day. Similar results were also found in cohort studies, but not in the case control studies. Our results were consistent with the meta-analysis of cohort studies conducted by Yu et al. in 2011 [10], in which coffee drinking was associated with a reduced risk of cancer occurrence, including prostate cancer, in 11 organ sites. However, our results were inconsistent with those of Chang et al. [9], who found a significant positive (harmful) association in seven case–control studies and a null association in four cohort studies. The discrepancy between the case–control and cohort studies might be due to the potential bias of case–control studies, such as selection bias and recall bias. In fact, in several recent meta-analyses, coffee consumption has been proved to be associated with a reduction in the risk of various types of cancer, including liver cancer, colorectal cancer, and endometrial cancer [37–39]. The mechanisms by which coffee affects carcinogenesis remain unclear, but substantial research in animal models and cell culture systems has been devoted to the identification of coffee components that may be responsible for these observed associations. Coffee is a complex substance consisting of many compounds, several of which have been shown to have physiological effects [5]. Caffeine, a key component of coffee, has strong antioxidant properties [40] and the ability to prevent oxidative DNA damage, modify the apoptotic response, and reverse cell-cycle checkpoint functions [41–43]. In addition, coffee contains two specific diterpenes (cafestol and kahweal) that have been shown to produce a broad range of biochemical effects resulting in a reduction in the genotoxicity of several carcinogens [44]. Coffee is also a major source of chlorogenic acid, which can scavenge reactive oxygen species and protect against environmental carcinogenesis, according to Feng et al. [45]. Correspondingly, coffee consumption has been shown to be associated with higher adiponectin plasma levels in vivo

9

Cohort studies

4

3

Canada

Asian

10

11

High

Low

Quality of study

7 7

USA Europe

Study region

12

21

No. of studies

0.93 (0.82–1.04)

0.91 (0.85–0.97)

0.76 (0.48–1.04)

1.05 (0.81–1.28)

0.93 (0.87–0.99) 0.87 (0.78–0.97)

0.89 (0.84–0.95)

1.10 (0.95–1.26)

0.91 (0.86–0.97)

OR (95 % CI)

7.3

18.2

64.2

0.0

0.0 20.9

8.0

0.0

9.0

I2 (%)

Unstratified highest (the highest level of coffee consumption in each included study)

Case–control studies

Study design

All studies

Study type

4

5

0

2

4 3

4

5

9

No. of studies

0.90 (0.81–0.98)

0.98 (0.93–1.03)

–

1.05 (0.75–1.35)

0.96 (0.92–1.00) 1.03 (0.71–1.35)

0.96 (0.92–1.00)

1.04 (0.82–1.26)

0.96 (0.92–1.00)

OR (95 % CI)

0.0

0.0

–

0.0

46.7 0.0

0.0

0.0

0.0

I2 (%)

Stratified highest (US studies, C4 cups/ day; European studies, C5 cups/day)

3

4

1

2

2 2

4

3

7

No. of studies

1.02 (0.77–1.27)

0.99 (0.95–1.04)

0.63 (0.32–0.94)

1.04 (0.68–1.40)

1.00 (0.95–1.05) 1.03 (0.82–1.25)

0.99 (0.94–1.04)

1.07 (0.87–1.27)

0.99 (0.95–1.04)

OR (95 % CI)

0.0

51.4

–

0.0

0.0 0.0

52.7

0.0

16.8

I2 (%)

Second highest (US studies 2–3 or C2 cups/day; European studies 3–4 or C3 cups/day)

Table 2 Odds ratios (OR) with 95 % confidence interval (95 % CI) of prostate cancer by category of total coffee intake

4

6

1

2

3 4

6

4

10

No. of studies

0.95 (0.86–1.04)

1.01 (0.97–1.04)

0.82 (0.62–1.08)

0.84 (0.61–1.08)

1.01 (0.97–1.04) 1.00 (0.84–1.17)

1.00 (0.97–1.04)

0.94 (0.77–1.10)

0.99 (0.95–1.03)

OR (95 % CI)

0.0

24.4

–

0.0

23.1 0.0

7.7

0.0

0.0

I2 (%)

Third highest (US studies, B1 cup/day; European studies, 1–2 cups/day)

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Cancer Causes Control Table 3 Odds ratios (ORs) with 95 % confidence interval (95 % CI) of coffee consumption and prostate cancer stage and grade Prostate cancer stage and grade

No. of studies

Fixed-effects model OR (95 % CI)

Random-effects model OR (95 % CI)

I2 (%)

Localized

6

0.89 (0.83–0.96)

0.89 (0.83–0.96)

0.0

Advanced

6

0.82 (0.69–0.96)

0.85 (0.58–1.12)

68.9

Fatal

4

0.64 (0.47–0.80)

0.66 (0.43–0.90)

47.8

Gleason \7

6

1.06 (0.86–1.25)

1.06 (0.86–1.25)

0.0

Gleason 7–10

6

0.66 (0.51–0.81)

0.68 (0.50–0.86)

20.2

[46–48]. As an endogenous insulin sensitizer [49], high coffee levels lead to decreased concentrations of both plasma insulin and insulin-like growth factor 1 (IGF-1); insulin levels have been observed to be directly associated with prostate cancer specific mortality [50, 51]. Therefore, ingredients in coffee may play an important role in protecting against the occurrence and development of prostate cancer. However, as the components contained in coffee occur in relatively low amounts, their protective effects are too small to observe in low-dose consumption. That may be the reason most studies observed an inverse relationship between high

Fig. 2 Forest plots of investigating association for various categories of coffee consumption with prostate cancer risk (fixed-effects model) stratified by study design for the following subgroups: a unstratified highest category (The highest level of coffee consumption in each included study); b stratified highest category (US studies, C4 cups/

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coffee consumption and prostate cancer risk, whereas no association was found in low or moderate intake, including our meta-analysis. In subgroup analyses by study region, there was an inverse association between high coffee consumption and prostate cancer among USA and European populations, and the significant risk reduction was stronger in European populations. The different results indicate that ethnicity might have an important effect on coffee metabolism. For instance, Nacetyltransferase 2 (NAT2) plays an important role in caffeine metabolism [5], and numerous polymorphisms of the gene for NAT2 that affect its acetylation activity have been identified [52]. A genetic polymorphism in the NAT2 gene leads to ‘‘fast acetylators’’ and ‘‘slow acetylators’’; the latter are actually unable to acetylate paraxanthine, which is the primary caffeine metabolite. Cytochrome P450 2A6 is an enzyme in coffee biotransformation [5], and a number of distinct polymorphisms that affect its activity have been reported, some of which might affect smoking behavior and cancer risk [53, 54]. Furthermore, differences in coffee drinking habits might partially explain the discrepancy. To further explore the relationship between coffee consumption and prostate cancer stage and Gleason grade,

day; European studies, C5 cups/day); c second highest category (US studies, 2–3 or C2 cups/day; European studies, 3–4 or C3 cups/day); and d third highest category (US studies, B1 cup/day; European studies, 1–2 cups/day)

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Fig. 3 Begg’s funnel plots and Egger’s test to detect publication bias in associations between coffee intake and prostate cancer risk. Each point represents a separate study. This was done for the following subgroups: a unstratified highest category (The highest level of coffee consumption in each included study); b stratified highest category

(US studies, C4 cups/day; European studies, C5 cups/day); c second highest category (US studies, 2–3 or C2 cups/day; European studies, 3–4 or C 3 cups/day); and d third highest category (US studies, B1 cup/day; European studies, 1–2 cups/day). OR odds ratio, SE standard error. p \ 0.05 suggests a significant publication bias

we conducted a subgroup meta-analysis. Six studies included in our overall meta-analysis reported the prostate cancer grade, and six included prostate cancer stage. Interestingly, our result indicated a significant inverse association between unstratified highest coffee consumption and the risk of fatal prostate cancer (OR 0.64, 95 % CI 0.47–0.80) and high-grade prostate cancer (Gleason 7–10: OR 0.66, 95 % CI 0.51–0.81). Our results were consistent with the cohort study in 2011 and case–control study in 2013 by Wilson et al. [14, 17], and their cohort study results were adjusted for an important confounder–PSA testing history. Two meta-analyses, conducted recently by Discacciati et al. [55] and Zhong et al. [56], were also found a significant inverse association between coffer consumption and fatal prostate cancers, as well as highgrade prostate cancers. Several plausible mechanisms might be responsible for this relationship, including coffee’s effects on serum insulin level [57], its antioxidant properties [40] and anti-inflammatory effects [48], and its possible effect on sex hormone levels [57]. As mentioned previously, insulin levels have been observed to be directly associated with a greater risk of cancer progression or

prostate cancer specific mortality [50, 51, 58]. Tumor progression might be promoted through insulin and IGF-1 receptors in cancer cells. IGF-1, a potent stimulator of normal and neoplastic cell growth, has antiapoptotic effects on prostate epithelial cells [59]. The direct association between IGF-1 and prostate cancer risk was observed in a pooled analysis of 12 prospective studies [60]. In addition, it was reported that circulating levels of IGF-I might predict the risk of developing advanced-stage prostate cancer [61]. Inflammation also plays an important role in the development of prostate cancer, through the generation of proliferative inflammatory atrophy lesions [62]. Coffee is a major source of antioxidant intake in several populations [4, 63], and dietary antioxidants may reduce inflammation and thus are associated with lower risk of advanced prostate cancer. More importantly, oxidative stress is a key event in the initiation, development, and progression of prostate cancer, and it has been found in preclinical studies that antioxidants could slow or prevent the progression of prostate cancer [64]. In accordance with these findings, special attention has been given to anti-inflammatory and antioxidant approaches to prostate cancer prevention [65].

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Finally, coffee consumption is an independent contributor to the variation of total testosterone and sex hormonebinding globulin (SHBG) [66]. Sex hormones play a role in prostate cancer, and an inverse association between SHBG levels and prostate cancer incidence was found in a pool analysis of 18 prospective studies [67]. In sum, the relationship between coffee and lowered risk of fatal and more advanced prostate cancer is biologically possible, but we failed to observe a significant relationship between coffee intakes and advanced prostate cancer, mainly due to heterogeneity. Regarding localized prostate cancer, a study by Discacciati et al. [13] reported a clear inverse association between coffee consumption and risk of localized prostate cancer; thus, accounting for our result that coffee consumption reduces the risk of localized prostate cancer. Because there are considerably fewer studies about coffee consumption and prostate cancer stage and grade, more and larger studies should be conducted to confirm these results. There were some merits to the current meta-analysis. First, the number of total cases included in the meta-analysis (472,493) has greater statistical power than a small sample size substantially, and our results were consistent with those of the previous meta-analysis conducted by Yu et al. [10]. Second, our study investigated the relationship between coffee consumption and prostate cancer stage and grade and found a significant inverse association between high coffee intake and the risk of fatal and high-grade prostate cancer. Third, we extracted the RRs/ORs/HRs for every category of coffee intake and conducted separate meta-analyses for different levels of consumption; thus, we derived a more precise estimation of the relationship between dose-dependent effects of coffee intake and prostate cancer risk. In spite of these advantages, some limitations of this metaanalysis should be acknowledged. The first limitation is misclassification of coffee intake. Most of the studies included in our meta-analysis did not provide information on coffee type, serving size, or brewing method. However, cup size could vary considerably, depending on the population. The standard coffee cup size is reported to be larger in the United States compared with Europe or Japan [68, 69]. In addition, the chemical component content of different coffees can obviously vary according to different serving sizes or brewing methods [70]. Therefore, differential misclassification could bias the results. Second, although all of the individual studies included had adjusted for important confounders for prostate cancer, unmeasured variables might have influenced their results. Third, most of the studies included in our meta-analysis were performed in America, Canada, and Europe. Further studies are needed in other ethnic populations to generalize the findings. Fourth, only six studies reported the prostate cancer grade, and four reported fatal prostate cancer stage; these numbers may be too small

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to draw a precise conclusion. Fifth, the sources of heterogeneity in the subgroups were not investigated. Heterogeneity can occur for various reasons, including differences in coffee classification (detail or rough), in the studied populations (e.g., ethnicity), or in sample selection (e.g., diagnosed criteria of cases, source of controls), as well as adjustments for other confounding factors. In our subgroup analysis of Asian studies, we found that two studies classified coffee intake into two categories, roughly as ‘‘Yes’’ or ‘‘No,’’ which might be the source of heterogeneity in the Asian studies. In addition, in our subgroup analysis of the second highest category of coffee consumption, both ‘‘cohort studies’’ in study region and ‘‘high’’ studies in quality of study consisted of different populations, and the study by Li et al. [15] did not adjust for any confounders; these factors may be responsible for the existence of heterogeneity. Sixth, only published studies were included in our meta-analysis; potential publication bias might influence the findings, although publication bias was observed only in the unstratified highest category model.

Conclusion Our meta-analysis suggests that high (C4 or 5 cups/day) coffee consumption might not be only associated with a reduced risk of overall prostate cancer, but also inversely associated with fatal and high-grade prostate cancer. However, because of potential confounding, these findings should be treated with caution. It is necessary to conduct large sample studies using more accurate questionnaires or other advanced methods to assess specific types and amounts of coffee intake, as well as different prostate cancer stages and grades. Such studies, taking these factors into account, may eventually lead to a better, more comprehensive understanding of the association between coffee consumption and prostate cancer. Conflict of interest of interest.

The authors declare that they have no conflict

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