Use of Biomarkers in Screening for Cancer.
BACKGROUND
Screening for premalignant lesions or early invasive disease has the potential to reduce mortality from cancer. Potential screening tests for malignancy include measurement of (bio)markers.


BACKGROUND
The literature relevant to the use of biomarkers as screening tests for cancer was reviewed with particular attention given to systematic reviews, prospective randomised trials and guidelines published by Expert Panels. Because of their ease of measurement, several biomarkers have been evaluated or are currently undergoing evaluation as screening tests for early malignancy. These include the use of vanillymandelic acid and homovanillic acid in screening for neuroblastoma in newborn infants, AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for ovarian cancer, PSA in screening for prostate cancer and fecal occult blood testing (FOBT) in screening for CRC. Of these markers, only the use of FOBT in screening for CRC has been shown to reduce mortality from cancer. Large randomized prospective trials are currently in progress aimed at evaluating the potential value of PSA screening in reducing mortality from prostate cancer and CA 125 in combination with TVU in reducing mortality form ovarian cancer.


CONCLUSIONS
Although biomarkers have many attractions as screening tests, inadequate sensitivity and specificity, when combined with the low prevalence of cancer in asymptomatic subjects, limit their value for the early detection of malignancy. Screening has been defined as the systematic application of a test to identify subjects at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, among persons who have not sought medical attention on account of symptoms of that disorder (1). To be of value, screening must detect disease earlier and result in an efficacious treatment and the earlier use of efficacious treatment must lead to better outcome compared to treatment available at the onset of symptoms (2). Screening differs from diagnosis in that the aim is to detect disease or a predisease state when subjects are asymptomatic. Currently, only a small number of screening tests have been shown to reduce mortality from cancer. These include mammography in screening for breast cancer (especially in women >50 years of age), the Papanicalaou (PAP) test in screening for cervical cancer and fecal occult blood testing (FOBT) in screening for colorectal cancer (CRC) (for review, see refs. 2,3). Compared to procedures such as radiology, cytology and endoscopy, the use of biomarkers as cancer screening tests have several advantages (4). These advantages include: Biomarkers can be measured in biological fluids such as blood and urine that can be obtained with minimal inconvenience to subjects undergoing screening. This in turn should lead to high compliance rates.For many biomarkers, automated assays are available, thus allowing the processing of large numbers of samples in a relatively short period of time.Tests for biomarkers provide quantitative results with objective endpoints.Assays for biomarkers are relatively cheap.In practice however, lack of sensitivity for early invasive disease or premalignant lesions and lack of specificity for malignancy limit the use of existing biomarkers in screening asymptomatic subjects for early malignancy (4,5). This lack of sensitivity and specificity when combined with the low prevalence of cancers in the general population means that most biomarkers, if used alone, have a low positive predictive value in screening asymptomatic populations. Indeed, it is the low prevalence of cancer in the general population that prohibits most biomarkers from being used alone, in screening for cancer (4,5). Despite these limitations, a number of biomarkers have either undergone or are currently undergoing evaluation as potential cancer screening tests. These markers include the use of vanillymandelic acid (VMA) and homovanillic acid (HVA) in screening for neuroblastoma in newborns, AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for ovarian cancer, PSA in screening for prostate cancer and fecal occult blood testing (FOBT) in screening for CRC. The aim of this article is to critically review the role of these biomarkers in screening normal-risk asymptomatic subjects for early cancer. Screening subjects with a genetic predisposition to cancer will not be discussed.
Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin 4, UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin , Dublin 4, Ireland.
Michael J
MJ
Duffy
Ann Intern Med. 2008 Oct 7;149(7):441-50, W81
18838724
Clin Chem. 2010 Jun;56(6):e1-48
20207771
Prostate. 2004 May 15;59(3):311-8
15042607
Lancet. 2008 Apr 5;371(9619):1173-80
18395578
J Med Screen. 2001;8(1):56
11373852
Eur J Cancer. 2007 Jun;43(9):1348-60
17512720
Prostate. 2004 Dec 1;61(4):371
15503321
J Natl Compr Canc Netw. 2009 Apr;7(4):350-91
19406039
Hepatology. 2005 Nov;42(5):1208-36
16250051
Best Pract Res Clin Obstet Gynaecol. 2002 Aug;16(4):469-82
12413929
Lancet. 1997 Jan 11;349(9045):113-7
8996432
J Cancer Res Clin Oncol. 2004 Jul;130(7):417-22
15042359
Prostate. 1999 Jul 1;40(2):130-4
10386474
Crit Rev Clin Lab Sci. 2001 Jun;38(3):225-62
11451209
N Engl J Med. 2009 Jul 9;361(2):170-7
19587342
J Natl Cancer Inst. 2007 Oct 3;99(19):1462-70
17895475
N Engl J Med. 2009 Mar 26;360(13):1310-9
19297565
J Clin Oncol. 2003 May 15;21(10 Suppl):206s-210s
12743136
Lancet Oncol. 2009 Apr;10(4):327-40
19282241
Lancet. 2008 Apr 5;371(9619):1142-3
18395561
Lancet. 1991 Feb 9;337(8737):344-6
1671243
N Engl J Med. 1996 Jan 18;334(3):155-9
8531970
N Engl J Med. 2009 Mar 26;360(13):1320-8
19297566
Eur Urol. 2004 Dec;46(6):717-23; discussion 724
15548438
JAMA. 1995 Feb 8;273(6):491-7
7837369
Hepatology. 2002 Nov;36(5 Suppl 1):S84-92
12407580
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001216
17253456
Ann Intern Med. 2008 Nov 4;149(9):627-37
18838716
Cancer Causes Control. 2005 Mar;16(2):171-88
15868457
Nat Rev Cancer. 2006 Sep;6(9):674-87
16929323
Cancer Res. 2000 Nov 1;60(21):5954-8
11085511
Br J Obstet Gynaecol. 1998 Nov;105(11):1136-47
9853761
Obstet Gynecol. 2009 Apr;113(4):775-782
19305319
J Med Screen. 1999;6(2):108-10
10444731
N Engl J Med. 2009 Mar 26;360(13):1351-4
19297564
J Med Screen. 2003;10(4):204-9
14738659
CA Cancer J Clin. 2007 Mar-Apr;57(2):90-104
17392386
N Engl J Med. 2002 Apr 4;346(14):1047-53
11932471
Prostate. 2004 Dec 1;61(4):372; author reply 373-4
15503318
J Clin Oncol. 2005 Nov 1;23(31):7919-26
16258091
Gastroenterology. 2005 Aug;129(2):745-8
16083728
Br J Surg. 1990 Sep;77(9):961-2
2095760
Nat Rev Cancer. 2005 Mar;5(3):199-209
15738983
Prostate. 1999 Feb 1;38(2):83-91
9973093
Ann Oncol. 2009 May;20 Suppl 4:76-8
19454471
J Clin Oncol. 2005 Jan 10;23(2):293-300
15637392
CA Cancer J Clin. 2009 Jan-Feb;59(1):27-41
19147867
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
Int J Cancer. 2005 Nov 1;117(2):169-76
15880368
Lancet. 1999 Apr 10;353(9160):1207-10
10217079
Cancer. 2004 Sep 1;101(5):894-904
15329895
Int J Gynecol Cancer. 2005 Sep-Oct;15(5):679-91
16174214
Cancer. 1995 Nov 15;76(10 Suppl):2004-10
8634992
Nat Rev Cancer. 2004 Sep;4(9):707-17
15343277
N Engl J Med. 2004 Dec 23;351(26):2704-14
15616205
N Engl J Med. 2002 Apr 4;346(14):1041-6
11932470
Am J Med. 2007 Mar;120(3):194-202
17349437
J Natl Cancer Inst. 2001 Jul 18;93(14):1054-61
11459866
Oncology (Williston Park). 2000 Nov;14(11):1601-7; discussion 1608, 1613-6
11125943
Int J Cancer. 1997 May 16;71(4):552-5
9178807
Cancer Treat Res. 2002;107:61-97
11775462
Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004720
16856057
Am J Obstet Gynecol. 2005 Nov;193(5):1630-9
16260202
N Engl J Med. 2004 May 6;350(19):2010-1
15128908
CA Cancer J Clin. 2008 May-Jun;58(3):130-60
18322143
Int J Cancer. 2002 Jan 10;97(2):237-44
11774270
BMJ. 1993 Apr 17;306(6884):1030-4
8490497
Clin Chem. 2008 Dec;54(12):e11-79
19042984
Gastroenterology. 2003 Feb;124(2):544-60
12557158
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
J Urol. 1994 Nov;152(5 Pt 2):1905-9
7523735
Int J Biol Markers. 1998 Oct-Dec;13(4):216-20
10228904