Potential Use of Biomarkers to Augment Clinical Decisions for the Early Detection of Breast Cancer

Oncology & Hematology Review, 2014;10(2):103–9

Abstract:

Breast cancer remains a significant worldwide health problem, despite the fact that early detection is associated with excellent survival rates. Currently, a substantial proportion of breast cancers are not detected using routine screening. Therefore, there is a need to identify a technology that can improve the precision and accuracy of early breast cancer detection. Biomarkers are attractive in that they can potentially detect early cancers with high sensitivity, while distinguishing between benign disease and invasive cancers. Many commonly used serum biomarkers have limited use in screening assays for breast cancer as single agents due to the heterogeneous nature of breast cancer. However, the use of protein panels that detect multiple serum biomarkers offer the potential for enhanced sensitivity and specificity in a clinical setting. Recently, a serum biomarker test comprising five serum biomarkers for breast cancer was clinically validated and showed high sensitivity and specificity. Additional panels have been developed that combine serum protein biomarkers (SPB) and tumor-associated autoantibodies (TAb) to further enhance the clinical utility of the assay. Serum biomarkers are currently not the standard of care and are not recommended in any detection guidelines. However, tumor biomarkers are used in the breast cancer setting to determine the course of care. The purpose of this article is to review recent advances in SPB, TAb, and biomarkers used in breast cancer detection to provide a perspective on how these technologies may offer benefit when combined with current imaging modalities.

Keywords: Breast cancer, biomarkers, screening, protein panel, early diagnosis
Disclosure: Alan B Hollingsworth, MD, is a consultant for Provista Diagnostics, Inc. David E Reese, PhD, is an employee of Provista Diagnostics, Inc.
Acknowledgments: Editorial assistance was provided by Katrina Mountfort, PhD, at Touch Medical Media, London, UK, and was funded by Provista Diagnostics, Inc.
Received: September 30, 2014 Accepted November 12, 2014 Citation Oncology & Hematology Review, 2014;10(2):103–9
Correspondence: Alan B Hollingsworth, MD, Mercy Women’s Center, 4300 McAuley Blvd, Oklahoma City, OK 73120, US (E: alan.hollingsworth@mercy.net). David E Reese, PhD, Provista Diagnostics, Inc., 160 Varick Street, 11th FL, New York, NY 10013, US (E: info@ProvistaDx.com).
Support: The publication of this article was supported by Provista Diagnostics, Inc. The views and opinions expressed are those of the authors and do not necessarily reflect those of Provista Diagnostics, Inc.

Breast cancer is the most common malignant disease in women: according to US statistics, one in eight women will be diagnosed with breast cancer in her lifetime.1 It was estimated that approximately 232,340 new cases of invasive breast cancer and 39,620 deaths were expected among US women in 2013.2 Early detection and diagnosis of breast cancer are essential for successful treatment; women diagnosed with stage II and III breast cancer have a high risk for recurrence and a higher chance of developing metastatic disease, which remains incurable.3 Early diagnosis of breast cancer is associated with significantly lower morbidity; tumor detection at stages 0 and 1 is associated with approximately 98 % 5-year survival.4

The study of biomarkers in the monitoring of tumor progression began with the discovery of carcinoembryonic antigen (CEA) in 1965.5 Biomarkers are potentially useful in screening programs, but the application of biomarker testing requires the incorporation of radiologic screening methods in order to locate the tumor for further treatment/assessment. Biomarkers can also be used in the diagnostic workup of suspicious lesions as part of the clinical decision-making process, and may provide biochemical evidence to inform decisions regarding the need for biopsy, much like positron emission tomography and computerized tomography (PET-CT) that measures the metabolic rate of a mass in conjunction with its anatomical presentation. The third potential use is to monitor for breast cancer disease recurrence. This article will outline the limitations of current breast cancer diagnostic methods and examine the role of biomarkers in current screening paradigms.

Limitations of Current Breast Cancer Screening Techniques and the Potential Role of Biomarkers
Current screening in the US for breast cancer relies heavily on mammography, which is an oversold and expensive regimen that detects only 70 % of breast cancers,6 while studies of multimodality imaging suggest that mammographic sensitivity is below 50 %.7 Mammographic screening is less effective in younger women. In 2009, the US Preventive Services Task Force (USPSTF) gave mammography a ‘C’ recommendation (routine screening not recommended) for women aged 40–49,8 largely because most diagnostic pathways are associated with false positives, causing anxiety and increased expense. The USPSTF suggested a ‘C’ recommendation despite the fact that their meta-analysis demonstrated a 15 % relative reduction in mortality with screening in this age group; they considered the harmful effects to be greater than the relatively small absolute benefit. The most recent update of the Canadian National Breast Screening Study presented a pessimistic scenario of mammographic screening. Annual mammography in women aged 40–59 did not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer was freely available.9 Importantly, Canadian data prior to this recent study were included in the 2009 meta-analysis performed by the USPSTF. This meta-analysis concluded that most of the historic screening trials showed a benefit to screening women aged 40–49, overriding the ‘no benefit’ statistical influence of the Canadian trial. It should be noted that the Canadian trial has been controversial in the community due to corruption of the randomization process and inclusion of palpable masses in the mammography trial.

References:
  1. DeSantis C, Ma J, Bryan L, et al., Breast cancer statistics, 2013, CA Cancer J Clin, 2014;64:52–62.
  2. Siegel R, Naishadham D, Jemal A, Cancer statistics, 2013, CA Cancer J Clin, 2013;63:11–30.
  3. Carlson RW, Allred DC, Anderson BO, et al., Breast cancer. Clinical practice guidelines in oncology, J Natl Compr Canc Netw, 2009;7:122–92.
  4. Early Breast Cancer Trialists’ Collaborative G, Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials, Lancet, 2005;365:1687–717.
  5. Gold P, Freedman SO, Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques, J Exp Med, 1965;121:439–62.
  6. Esserman L, Shieh Y, Thompson I, Rethinking screening for breast cancer and prostate cancer, JAMA, 2009;302:1685–92.
  7. Sardanelli F, Podo F, Breast MR imaging in women at high-risk of breast cancer. Is something changing in early breast cancer detection?, Eur Radiol, 2007;17:873–87.
  8. US preventative Services Task Force. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms, 2009. Available at: http://www.uspreventiveservicestaskforce.org/uspstf09/ breastcancer/brcanart.htm (accessed November 12, 2014).
  9. Miller AB, Wall C, Baines CJ, et al., Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, BMJ, 2014;348:g366.
  10. Weedon-Fekjær H, Romundstad PR, Vatten LJ, Modern mammography screening and breast cancer mortality: population study, BMC, 2014;348:g3701.
  11. Independent UKPoBCS, The benefits and harms of breast cancer screening: an independent review, Lancet, 2012;380:1778–86.
  12. Esserman LJ, Shieh Y, Park JW, et al., A role for biomarkers in the screening and diagnosis of breast cancer in younger women, Expert Rev Mol Diagn, 2007;7:533–44.
  13. Schrading SS, Strobel K, Kuhl CK, MRI screening of women at average risk of breast cancer, J Clin Oncol, 2013;31:abstr 21.
  14. Hillman BJ, Harms SE, Stevens G, et al., Diagnostic performance of a dedicated 1.5-T breast MR imaging system, Radiology, 2012;265:51–8.
  15. Taneja C, Edelsberg J, Weycker D, et al., Cost effectiveness of breast cancer screening with contrast-enhanced MRI in highrisk women, ACJ Am Coll Radiol, 2009;6:171–9.
  16. Kriege M, Brekelmans CT, Boetes C, et al., Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition, N Engl J Med, 2004;351:427–37.
  17. Lehman CD, Blume JD, Weatherall P, et al., Screening women at high risk for breast cancer with mammography and magnetic resonance imaging, Cancer, 2005;103:1898–905.
  18. Sardanelli F, Podo F, D’Agnolo G, et al., Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study): interim results, Radiology, 2007;242:698–715.
  19. Leach MO, Boggis CR, Dixon AK, et al., Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS), Lancet, 2005;365:1769–78.
  20. Kuhl CK, Schrading S, Leutner CC, et al., Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer, J Clin Oncol, 2005;23:8469–76.
  21. Warner E, Plewes DB, Hill KA, et al., Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination, JAMA, 2004;292:1317–25.
  22. NCCN, Practice guidelines in oncology. breast cancer screening and diagnosis. Version 1.2012. Available at: http://www.nccn. org/professionals/physician_gls/PDF/breast-screening.pdf (accessed June 17, 2014).
  23. Lee CH, Dershaw DD, Kopans D, et al., Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer, J Am Coll Radiol, 2010;7:18–27.
  24. Hollingsworth AB, Stough RG, An alternative approach to selecting patients for high-risk screening with breast MRI, Breast J, 2014;20:192–-7.
  25. Berg WA, Zhang Z, Lehrer D, et al., Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk, JAMA, 2012;307:1394–404.
  26. ACR BI-RADS, Mammography. In: ACR Breast Imaging Reporting and Data System, Breast Imaging Atlas, 4th edn. Reston, VA: American College of Radiology, 2003:179–80.
  27. Lacquement MA, Mitchell D, Hollingsworth AB, Positive predictive value of the Breast Imaging Reporting and Data System, J Am Coll Surg, 1999;189:34–40.
  28. Duffy MJ, Serum tumor markers in breast cancer: are they of clinical value?, Clin Chem, 2006;52:345–51.
  29. Harris L, Fritsche H, Mennel R, et al., American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer, J Clin Oncol, 2007;25:5287–312.
  30. Cronin M, Sangli C, Liu ML, et al., Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer, Clin Chem, 2007;53:1084–91.
  31. Nielsen T, Wallden B, Schaper C, et al., Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffinembedded breast tumor specimens, BMC Cancer, 2014;14:177.
  32. Drukker CA, Schmidt MK, Rutgers EJ, et al., Mammographic screening detects low-risk tumor biology breast cancers, Breast Cancer Res Treat, 2014;144:103–11.
  33. Rutgers E, Piccart-Gebhart MJ, Bogaerts J, et al., The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase, Eur J Cancer, 2011;47:2742–9.
  34. Isaacs C, Stearns V, Hayes DF, New prognostic factors for breast cancer recurrence, Semin Oncol, 2001;28:53–67.
  35. LH, Herbert BS, Abdel-Aziz W, et al., A cancer-associated PCNA expressed in breast cancer has implications as a potential biomarker, Proc Natl Acad Sci U S A, 2006;103:19472–7.
  36. Guadagni F, Ferroni P, Carlini S, et al., A re-evaluation of carcinoembryonic antigen (CEA) as a serum marker for breast cancer: a prospective longitudinal study, Clin Cancer Res, 2001;7:2357–62.
  37. Wang DY, Knyba RE, Bulbrook RD, et al., Serum carcinoembryonic antigen in the diagnosis and prognosis of women with breast cancer, Eur J Cancer Clin Oncol, 1984;20:25–31.
  38. Incoronato M, Mirabelli P, Catalano O, et al., CA15-3 is a useful serum tumor marker for diagnostic integration of hybrid positron emission tomography with integrated computed tomography during follow-up of breast cancer patients, BMC Cancer, 2014;14:356.
  39. Lauro S, Trasatti L, Bordin F, et al., Comparison of CEA, MCA, CA 15-3 and CA 27-29 in follow-up and monitoring therapeutic response in breast cancer patients, Anticancer Res, 1999;19:3511–5.
  40. Rack B, Schindlbeck C, Juckstock J, et al., Prevalence of CA 27.29 in primary breast cancer patients before the start of systemic treatment, Anticancer Res, 2010;30:1837–41.
  41. Leyland-Jones B, Smith BR, Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls, Lancet Oncol, 2011;12:286–95.
  42. Carney WP, Neumann R, Lipton A, et al., Monitoring the circulating levels of the HER2/neu oncoprotein in breast cancer, Clin Breast Cancer, 2004;5:105–16.
  43. Le Naour F, Misek DE, Krause MC, et al., Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer, Clin Cancer Res, 2001;7:3328–35.
  44. Hammond ME, Hayes DF, Wolff AC, et al., American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer, J Oncol Pract, 2010;6:195–7.
  45. Look M, van Putten W, Duffy M, et al., Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients, Thromb Haemost, 2003;90:538–48.
  46. Anderson KS, Ramachandran N, Wong J, et al., Application of protein microarrays for multiplexed detection of antibodies to tumor antigens in breast cancer, J Proteome Res, 2008;7:1490–9.
  47. Anderson KS, Sibani S, Wallstrom G, et al., Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer, J Proteome Res, 2011;10:85–96.
  48. Jager D, Unkelbach M, Frei C, et al., Identification of tumorrestricted antigens NY-BR-1, SCP-1, and a new cancer/testis-like antigen NW-BR-3 by serological screening of a testicular library with breast cancer serum, Cancer Immun, 2002;2:5.
  49. Stockert E, Jager E, Chen YT, et al., A survey of the humoral immune response of cancer patients to a panel of human tumor antigens, J Exp Med, 1998;187:1349–54.
  50. Lu H, Ladd J, Feng Z, et al., Evaluation of known oncoantibodies, HER2, p53, and cyclin B1, in prediagnostic breast cancer sera, Cancer Prev Res (Phila), 2012;5:1036–43.
  51. Jager D, Knuth A, Antibodies and vaccines—hope or illusion?, Breast, 2005;14:631–5.
  52. Robinson WH, DiGennaro C, Hueber W, et al., Autoantigen microarrays for multiplex characterization of autoantibody responses, Nat Med, 2002;8:295–301.
  53. Chapman C, Murray A, Chakrabarti J, et al., Autoantibodies in breast cancer: their use as an aid to early diagnosis, Ann Oncol, 2007;18:868–73.
  54. Litvak DA, Gupta RK, Yee R, et al., Endogenous immune response to early- and intermediate-stage melanoma is correlated with outcomes and is independent of locoregional relapse and standard prognostic factors, J Am Coll Surg, 2004;198:27–35.
  55. Scanlan MJ, Welt S, Gordon CM, et al., Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets, Cancer Res, 2002;62:4041–7.
  56. Shiomi-Mouri Y, Kousaka J, Ando T, et al., Clinical significance of circulating tumor cells (CTCs) with respect to optimal cut-off value and tumor markers in advanced/metastatic breast cancer, Breast Cancer, 2014 [Epub ahead of print].
  57. Derin D, Soydinc HO, Guney N, et al., Serum IL-8 and IL-12 levels in breast cancer, Med Oncol, 2007;24:163–8.
  58. Zakrzewska I, Kozlowski L, Wojtukiewicz M, [Value of interleukin-8 determination in diagnosis of benign and malignant breast tumor], Pol Merkur Lekarski, 2002;13:302–4. 59. Weber D, Grimes R, Su P, et al., Age-stratification’s role in cytokine based assay development, Anal Methods, 2010;2:653–6.
  59. Zhu H, Bilgin M, Bangham R, et al., Global analysis of protein activities using proteome chips, Science, 2001;293:2101–5.
  60. Petricoin E, Wulfkuhle J, Espina V, et al., Clinical proteomics: revolutionizing disease detection and patient tailoring therapy, J Proteome Res, 2004;3:209–17.
  61. Wulfkuhle JD, McLean KC, Paweletz CP, et al., New approaches to proteomic analysis of breast cancer, Proteomics, 2001;1:1205–15.
  62. Henderson MC, Sweeten K, Borman S, et al., DtectDx Breast: A serum biomarker test for breast cancer detection used in conjunction with traditional mammography screening, J Clin Oncol, 2013;31:Suppl. 26; abstr. 18.
  63. Breast cancer biomarker sample collection for the dtectDx assay verification, Provista Diagnostics. Available at: http:// clinicaltrials.gov/show/NCT01839045 (accessed June 12, 2014).
  64. Breast cancer biomarker sample collection for the dtectDx v2 assay proof of concept protocol, Provista Diagnostics, Inc. Available at: http://clinicaltrials.gov/ct2/show/NCT02078570?ter m=Provista+breast+cancer&rank=2 (accessed June 12, 2014).
  65. Kulasingam V, Diamandis EP, Strategies for discovering novel cancer biomarkers through utilization of emerging technologies, Nat Clin Pract Oncol, 2008;5:588–99.
Keywords: Breast cancer, biomarkers, screening, protein panel, early diagnosis