Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial

Bora Gurel; M. Scott Lucia; Ian M. Thompson; Phyllis J. Goodman; Catherine M. Tangen; Alan R. Kristal; Howard L. Parnes; Ashraful Hoque; Scott M. Lippman; Siobhan Sutcliffe; Sarah B. Peskoe; Charles G. Drake; William G. Nelson; Angelo M. De Marzo; Elizabeth A. Platz

doi:10.1158/1055-9965.EPI-13-1126

DOI: 10.1158/1055-9965.EPI-13-1126 Published May 2014

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Figure 1.
Scoring of chronic inflammation in prostate biopsy cores by severity (grade) and tissue compartment. All images are of benign areas obtained as screen shots from whole slide scanned images. A to C, increasing severity of inflammation in the stroma; D to F, increasing severity of intraepithelial inflammation; G to I, increasing severity of intraluminal inflammation. A to F, original magnification ×100. G to I, original magnification ×200.
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Figure 2.
Association between at least one biopsy core with inflammation and total and high-grade prostate cancer overall and when restricting the analysis to cases and controls with lower PSA concentration (<2 ng/mL) at biopsy.

Tables

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Table 1.

Characteristics^a of prostate cancer cases and controls^b, placebo arm, and the PCPT

		Prostate cancer cases
	Controls	Total	Low-grade	High-grade
N	209	191	97	94
Mean age at baseline (y)	63.9	63.6	62.7	64.6
Mean age at biopsy (y)	70.8	70.1^c	70.2^c	70.1^c
Non-White (%)	16.3	8.4	6.2^c	10.6
Family history (%)	17.7	16.2	15.5	17.0
Cigarette smoking history (%)
Current	5.9	7.2	5.5	8.9
Former	60.8	56.5	55.3	57.8
Never	33.3	36.3	39.2	33.3
Mean pack-years smoked, current and former smokers	24.7	21.0^c	19.6^c	22.2
Mean BMI (kg/m²)	27.4	27.5	27.2	27.9
History of diabetes (%)	9.1	5.8	4.4	7.2
Mean PSA
Concentration at baseline (ng/mL)	1.2	1.6^c	1.6^c	1.6^c
Concentration at biopsy (ng/mL)	2.1	3.3^c	3.0	3.7^c
Velocity (ng/mL/y)	0.11	0.27^c	0.20	0.34^c

↵^aFor all characteristics except baseline age, family history of prostate cancer, and race, from generalized linear models (linear for adjusted proportions and means and logistic for P values) adjusting for baseline age, family history, and race.
↵^bCases and controls were frequency matched on baseline age and family history. All non-White controls were sampled. Cases were sampled from the placebo arm of the trial so that half were high grade (Gleason sum ≥7) and half were low grade (Gleason sum <7), and of these half were detected on a biopsy performed for an elevated PSA or an abnormal DRE (for-cause biopsy) and half were detected on a biopsy performed at the end of the trial per trial protocol (end-of-study biopsy). Controls were sampled from men who were negative for prostate cancer on the biopsy performed at the end of the trial per protocol.
↵^cP < 0.05 compared with controls.

Table 2.

Prevalence and extent^a of inflammation assessed in benign prostate tissue from biopsy cores, prostate cancer cases overall and by grade and controls^b, placebo arm, and the PCPT

		Prostate cancer cases
	Controls	Total	Low-grade	High-grade
N	209	191	97	94
At least one biopsy core with inflammation (%)^c	78.2	86.2^e	84.0	88.4^e
Mean of the percentage of biopsy cores with inflammation^c	52.1	58.7	56.1	61.4^e
Mean of the mean percentage of tissue area with inflammation^d
Overall	11.5	10.9	10.8	10.9
In men with at least one biopsy core with inflammation	14.7	12.6	12.8	12.3

↵^aFrom generalized linear models (linear for adjusted proportions and means, logistic for P values) adjusting for baseline age, family history of prostate cancer, and race.
↵^bCases and controls were frequency matched on baseline age and family history of prostate cancer. All non-White controls were sampled. Cases were sampled from the placebo arm of the trial so that half were high grade (Gleason sum ≥7) and half were low grade (Gleason sum <7), and of these half were detected on a biopsy performed for an elevated PSA or an abnormal DRE (for-cause biopsy) and half were detected on a biopsy performed at the end of the trial per trial protocol (end-of-study biopsy). Controls were sampled from men who were negative for prostate cancer on the biopsy performed at the end of the trial per protocol.
↵^cFor each man, the denominator is total number of biopsy cores evaluated.
↵^dFor each man, the denominator is total benign tissue area across all biopsy cores evaluated on each of the slides of the man.
↵^eP < 0.05 compared with controls.

Table 3.

Association^a between inflammation assessed in benign prostate tissue from biopsy cores and prostate cancer risk, overall and by grade, placebo arm, and the PCPT

	Prostate cancer cases
	Total	Low-grade	High-grade
N	191	97	94
At least one biopsy core with inflammation
OR	1.78	1.57	2.24
95% CI	1.04–3.06	0.83–3.00	1.06–4.71
Extent of biopsy cores with inflammation^b
Zero cores
OR	1.00	1.00	1.00
95% CI	Reference	Reference	Reference
Some cores
OR	1.61	1.45	1.97
95% CI	0.92–2.81	0.74–2.84	0.91–4.26
All cores
OR	2.19	1.87	2.83
95% CI	1.18–4.06	0.88–3.94	1.24–6.44
P_trend	0.01	0.10	0.01

↵^aFrom the logistic regression model adjusting for the matching factors baseline age and family history of prostate cancer, and for the oversampling of non-White controls. Cases and controls were frequency matched on baseline age and family history of prostate cancer. All non-White controls were sampled. Cases were sampled from the placebo arm of the trial so that half were high grade (Gleason sum ≥7) and half were low grade (Gleason sum <7), and of these half were detected on a biopsy performed for an elevated PSA or an abnormal DRE (for-cause biopsy) and half were detected on a biopsy performed at the end of the trial per trial protocol (end-of-study biopsy). Controls were sampled from men who were negative for prostate cancer on the biopsy performed at the end of the trial per protocol.
↵^bA mean of three biopsy cores was assessed per man. Some cores with inflammation usually meant one or two, but not all three cores had inflammation present.

Table 4.

Mean serum PSA concentration at biopsy^a by prevalence and extent of inflammation assessed in benign prostate tissue from biopsy cores in the controls and prostate cancer cases, placebo arm, and the PCPT

	At least one biopsy core with inflammation			Extent of biopsy cores with inflammation
	No	Yes	P	Some	All	P_trend^b
Controls
Total (N)	46	163		109	54
Mean PSA at biopsy (ng/mL)	1.3	2.4	0.003	1.6	3.8	<0.0001
Without indication for biopsy (N)	42	149		102	47
Mean PSA at biopsy (ng/mL)	1.1	1.7	0.001	1.6	1.9	0.0002
Cases
Total (N)	26	165		100	65
Mean PSA at biopsy (ng/mL)	3.3	3.4	0.77	3.4	3.3	0.70
Detected on a for-cause biopsy (N)	11	83		50	33
Mean PSA at biopsy (ng/mL)	4.5	4.7	0.75	4.9	4.2	0.61
Detected on an end-of-study biopsy^c (N)	15	82		50	32
Mean PSA at biopsy (ng/mL)	2.4	2.0	0.45	1.9	2.3	0.32

↵^aFrom linear regression models adjusting for age at baseline.
↵^bAcross no (zero), some, all biopsy cores with inflammation. Reference is men with “No” (zero) biopsy cores with inflammation.
↵^cWithout an indication for biopsy.