Definition

A biomarker used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest.

Examples

• BReast CAncer genes 1 and 2 (BRCA1/2) mutations may be used as prognostic biomarkers when evaluating women with breast cancer, to assess the likelihood of a second breast cancer (Basu et al. 2015).
• Chromosome 17p deletions and TP53 mutations may be used as prognostic biomarkers when evaluating patients with chronic lymphocytic leukemia, to assess the likelihood of death (Gonzalez et al. 2011; Shanafelt et al. 2006).
• Increasing prostate-specific antigen (PSA) may be used as a prognostic biomarker when evaluating patients with prostate cancer during follow-up, to assess the likelihood of cancer progression (Roberts et al. 2001).
• Plasma fibrinogen may be used as a prognostic biomarker to select patients with chronic obstructive pulmonary disease at high risk for exacerbation and/or all-cause mortality for inclusion in interventional clinical trials (Miller et al. 2016; U.S. Food and Drug Administration 2016a).
• C-reactive protein (CRP) level may be used as a prognostic biomarker to identify patients with unstable angina or a history of acute myocardial infarction with a greater likelihood of recurrent coronary artery disease events (Ferreiros et al. 1999; Haverkate et al. 1997; Liuzzo et al. 1994; Nakachi et al. 2008; Pearson et al. 2003).
• Gleason score may be used as a prognostic biomarker when evaluating patients with prostate cancer to assess the likelihood of cancer progression (Epstein et al. 2016; Gordetsky and Epstein 2016).
• Total kidney volume may be used as a prognostic biomarker to select patients with autosomal dominant polycystic kidney disease at high risk for progressive decline in renal function for inclusion in interventional clinical trials (Grantham et al. 2006; U.S. Food and Drug Administration 2016b).

Explanation

A prognostic biomarker is one that indicates an increased (or decreased) likelihood of a future clinical event, disease recurrence or progression in an identified population. Prognostic biomarkers are measured at a defined baseline, which may include a background treatment. Many familiar examples of prognostic biomarkers occur in clinical contexts where an individual is diagnosed with a disease or condition and there is interest in assessing the likelihood of a future clinical event. Examples of future events include death, disease progression, disease recurrence, or development of a new medical condition. In oncology, biomarkers such as tumor size, number of lymph nodes positive for tumor cells, and presence of metastasis have traditionally been used to indicate prognosis. Increasingly, molecular indicators or signatures measured on tumors are being used in lieu of, or in addition to, these clinicopathologic characteristics. For patients who have previously suffered a heart attack, elevated blood pressure, evidence of diabetes, elevated LDL cholesterol, and low HDL cholesterol are examples of biomarkers that indicate an increased risk for another heart attack. For individuals with hypertension, concomitant evidence of diabetes is associated with an increased likelihood of cardiovascular events. The prognostic biomarker’s association with outcome is present without reference to different interventions (i.e., predicts increased likelihood of an event without an intervention). However, the presence or strength of a prognostic association may vary depending on the specific clinical setting (e.g., background therapy, stage of disease) and particular endpoint of interest, so it is important that prognostic biomarkers be described in the proper context.

Prognostic biomarkers are often used as eligibility criteria in clinical trials to identify patients who are more likely to have clinical events or disease progression. Thus, they are widely used as enrichment factors in drug development (U.S. Food and Drug Administration 2012). Many clinical trials of medical interventions have as their endpoint either an event rate or time-to-event. The statistical power for a time-to-event endpoint to assess treatment effect in a controlled clinical trial is driven by the planned effect size (i.e., hazard ratio for a time to event endpoint) and the planned number of events. Enrichment with patients who have a higher likelihood of experiencing an event will therefore increase statistical power. Analogous to this situation is the use of susceptibility/risk biomarkers for enrichment of prevention trial populations. In a treatment setting, prognostic biomarkers can contribute to decisions about whether or how aggressively to intervene with the treatment.

The term prognostic has not been used consistently in the biomedical community. Some have applied the term only in the clinical context of individuals who have already been diagnosed with a disease or other medical condition. Others would include among prognostic biomarkers those that indicate, for apparently healthy individuals, the likelihood of a future diagnosis or disease. This document makes a distinction between prognostic biomarker and susceptibility/risk biomarker, the latter defined here as applying to individuals without clinically apparent disease (or medical condition).

References

• Basu NN, Ingham S, Hodson J, Lalloo F, Bulman M, Howell A, Evans DG. Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis. Fam Cancer. 2015 Dec;14(4):531–8. [PubMed: 26239694] [CrossRef]
• Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. Grading Committee. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016 Feb;40(2):244–52. [PubMed: 26492179] [CrossRef]
• Ferreirós ER, Boissonnet CP, Pizarro R, Merletti PF, Corrado G, Cagide A, Bazzino OO. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation. 1999 Nov 9;100(19):1958–63. [PubMed: 10556221] [CrossRef]
• Gonzalez D, Martinez P, Wade R, Hockley S, Oscier D, Matutes E, Dearden CE, Richards SM, Catovsky D, Morgan GJ. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011 Jun 1;29(16):2223–9. [PubMed: 21483000] [CrossRef]
• Gordetsky J, Epstein J. Grading of prostatic adenocarcinoma: current state and prognostic implications. Diagn Pathol. 2016 Mar 9;11:25. [PMC free article: PMC4784293] [PubMed: 26956509] [CrossRef]
• Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, Wetzel LH, Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, Zhang X, Zhu F, Miller JP. CRISP Investigators. Volume progression in polycystic kidney disease. N Engl J Med. 2006 May 18;354(20):2122–30. [PubMed: 16707749] [CrossRef]
• Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997 Feb 15;349(9050):462–6. [PubMed: 9040576] [CrossRef]
• Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994 Aug 18;331(7):417–24. [PubMed: 7880233] [CrossRef]
• Miller BE, Tal-Singer R, Rennard SI, Furtwaengler A, Leidy N, Lowings M, Martin UJ, Martin TR, Merrill DD, Snyder J, Walsh J, Mannino DM. Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium. Am J Respir Crit Care Med. 2016 Mar 15;193(6):607–13. [PubMed: 26745765] [CrossRef]
• Nakachi T, Kosuge M, Hibi K, Ebina T, Hashiba K, Mitsuhashi T, Endo M, Umemura S, Kimura K. C-reactive protein elevation and rapid angiographic progression of nonculprit lesion in patients with non-ST-segment elevation acute coronary syndrome. Circ J. 2008 Dec;72(12):1953–9. [PubMed: 18957790] [CrossRef]
• Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F., Centers for Disease Control and Prevention. American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003 Jan 28;107(3):499–511. [PubMed: 12551878] [CrossRef]
• Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc. 2001 Jun;76(6):576–81. [PubMed: 11393495] [CrossRef]
• Shanafelt TD, Witzig TE, Fink SR, Jenkins RB, Paternoster SF, Smoley SA, Stockero KJ, Nast DM, Flynn HC, Tschumper RC, Geyer S, Zent CS, Call TG, Jelinek DF, Kay NE, Dewald GW. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol. 2006 Oct 1;24(28):4634–41. [PubMed: 17008705] [CrossRef]
• U.S. Food and Drug Administration. 2016a. Guidance for Industry: Qualification of Biomarker - Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease. September 14, 2016. Accessed October 2016. http://www​.fda.gov/downloads​/Drugs/GuidanceComplianceRegulatoryInformation​/Guidances/UCM453496.pdf.
• U.S. Food and Drug Administration. 2016b. Guidance for Industry: Qualification of Biomarker - Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease. September 15, 2016. Accessed October 2016. http://www​.fda.gov/downloads​/Drugs/GuidanceComplianceRegulatoryInformation​/Guidances/UCM458483.pdf.
• U.S. Food and Drug Administration. Draft Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. December 2012. Accessed 7 March 2016. http://www​.fda.gov/downloads​/drugs/guidancecomplianceregulatoryinformation​/guidances/ucm332181.pdf.