An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies


Autoři: Alexandre Perrier aff001;  Pierre-Yves Boelle aff002;  Yves Chrétien aff003;  Joseph Gligorov aff004;  Jean-Pierre Lotz aff004;  Didier Brault aff001;  Eva Comperat aff005;  Guillaume Lefèvre aff001;  Mathieu Boissan aff001
Působiště autorů: Laboratoire de Biochimie et Hormonologie, Hôpital Tenon, Groupe Hospitalier Est Parisien, Assistance Publique–Hôpitaux de Paris, Paris, France aff001;  Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (IPLESP), Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France aff002;  Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris, France aff003;  Service d’Oncologie Médicale, Institut Universitaire de Cancérologie APHP–Sorbonne Université, Paris, France aff004;  Department of Pathology, Hôpital Tenon, Groupe Hospitalier Est Parisien, Assistance Publique Hôpitaux de Paris, Paris, France aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227356

Souhrn

Background

The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer.

Methods

We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90.

Results

Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P<0.001, Se = 100%, Sp = 78%).

Conclusion

We show that regular measurement of sHER2, CA15.3, and CEA levels is useful for predicting the therapeutic response and for monitoring HER2-targeted therapy in patients with HER2-positive metastatic breast cancer. The average decrease of the three biomarkers with a threshold of > 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.

Klíčová slova:

Biomarkers – Breast cancer – Breast tumors – Cancer treatment – Immunohistochemistry techniques – Metastasis – Monoclonal antibodies – Progressive diseases


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 Feb;66(1):7–30. doi: 10.3322/caac.21332 26742998

2. Shah MV, Wiktor AE, Meyer RG, Tenner KS, Ballman KV, Green SJ, et al. Change in Pattern of HER2 Fluorescent in Situ Hybridization (FISH) Results in Breast Cancers Submitted for FISH Testing: Experience of a Reference Laboratory Using US Food and Drug Administration Criteria and American Society of Clinical Oncology and College of American Pathologists Guidelines. J Clin Oncol. 2016 Oct 10;34(29):3502–10. doi: 10.1200/JCO.2015.61.8983 27458302

3. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182. doi: 10.1126/science.3798106 3798106

4. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684. doi: 10.1056/NEJMoa052122 16236738

5. Swain SM, Baselga J, Kim S-B, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724–34. doi: 10.1056/NEJMoa1413513 25693012

6. Molina R, Auge JM, Farrus B, Zanón G, Pahisa J, Muñoz M, et al. Prospective evaluation of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) in patients with primary locoregional breast cancer. Clin Chem. 2010 Jul;56(7):1148–57. doi: 10.1373/clinchem.2009.135566 20472825

7. Duffy MJ. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem. 2006 Mar;52(3):345–51. doi: 10.1373/clinchem.2005.059832 16410341

8. Wu S-G, He Z-Y, Ren H-Y, Yang L-C, Sun J-Y, Li F-Y, et al. Use of CEA and CA15-3 to Predict Axillary Lymph Node Metastasis in Patients with Breast Cancer. J Cancer. 2016 Jan 1;7(1):37–41. doi: 10.7150/jca.13090 26722358

9. Park B-W, Oh J-W, Kim J-H, Park SH, Kim K-S, Kim JH, et al. Preoperative CA 15–3 and CEA serum levels as predictor for breast cancer outcomes. Ann Oncol. 2008 Apr;19(4):675–81. doi: 10.1093/annonc/mdm538 18037623

10. Lee J. S., Park S., Park J. M., Cho J. H., Kim S. I., and Park B.-W. “Elevated Levels of Preoperative CA 15–3 and CEA Serum Levels Have Independently Poor Prognostic Significance in Breast Cancer.” Annals of Oncology: Official Journal of the European Society for Medical Oncology 24, no. 5 (May 2013): 1225–31.

11. Di Gioia D, Dresse M, Mayr D, Nagel D, Heinemann V, Stieber P. Serum HER2 in combination with CA 15–3 as a parameter for prognosis in patients with early breast cancer. Clin Chim Acta. 2015 Feb 2;440:16–22. doi: 10.1016/j.cca.2014.11.001 25444743

12. Yang Y, Zhang H, Zhang M, Meng Q, Cai L, Zhang Q. Elevation of serum CEA and CA15-3 levels during antitumor therapy predicts poor therapeutic response in advanced breast cancer patients. Oncol Lett. 2017 Dec;14(6):7549–56. doi: 10.3892/ol.2017.7164 29344201

13. Robertson JF, Jaeger W, Syzmendera JJ, Selby C, Coleman R, Howell A, et al. The objective measurement of remission and progression in metastatic breast cancer by use of serum tumour markers. European Group for Serum Tumour Markers in Breast Cancer. Eur J Cancer. 1999 Jan;35(1):47–53. doi: 10.1016/s0959-8049(98)00297-4 10211087

14. Kurebayashi J, Nishimura R, Tanaka K, Kohno N, Kurosumi M, Moriya T, et al. Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: a prospective study. Breast Cancer. 2004;11(4):389–95. doi: 10.1007/bf02968047 15604995

15. Dixon AR, Jackson L, Chan SY, Badley RA, Blamey RW. Continuous chemotherapy in responsive metastatic breast cancer: a role for tumour markers? Br J Cancer. 1993 Jul;68(1):181–5. doi: 10.1038/bjc.1993.310 8318411

16. Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM, et al. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2015 Aug 20;33(24):2695–704. doi: 10.1200/JCO.2015.61.1459 26195705

17. Di Gioia D, Heinemann V, Nagel D, Untch M, Kahlert S, Bauerfeind I, et al. Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC). Tumour Biol. 2011 Aug;32(4):777–85. doi: 10.1007/s13277-011-0180-7 21553235

18. Perrier A, Gligorov J, Lefèvre G, Boissan M. The extracellular domain of Her2 in serum as a biomarker of breast cancer. Lab Invest. 2018 Jun;98(6):696–707. doi: 10.1038/s41374-018-0033-8 29491426

19. Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, et al. NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 1998 Nov 15;58(22):5123–9. 9823322

20. Reix N, Malina C, Chenard M-P, Bellocq J-P, Delpous S, Molière S, et al. A prospective study to assess the clinical utility of serum HER2 extracellular domain in breast cancer with HER2 overexpression. Breast Cancer Res Treat. 2016;160(2):249–59. doi: 10.1007/s10549-016-4000-z 27709352

21. Lam L, McAndrew N, Yee M, Fu T, Tchou JC, Zhang H. Challenges in the clinical utility of the serum test for HER2 ECD. Biochim Biophys Acta. 2012 Aug;1826(1):199–208. doi: 10.1016/j.bbcan.2012.03.012 22521738

22. Tsé C, Gauchez A-S, Jacot W, Lamy P-J. HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. Cancer Treat Rev. 2012 Apr;38(2):133–42. doi: 10.1016/j.ctrv.2011.03.008 21549508

23. Carney WP, Bernhardt D, Jasani B. Circulating HER2 Extracellular Domain: A Specific and Quantitative Biomarker of Prognostic Value in all Breast Cancer Patients? Biomark Cancer. 2013 Aug 12;5:31–9. doi: 10.4137/BIC.S12389 24179396

24. Sandri MT, Johansson H, Colleoni M, Zorzino L, Passerini R, Orlando L, et al. Serum levels of HER2 ECD can determine the response rate to low dose oral cyclophosphamide and methotrexate in patients with advanced stage breast carcinoma. Anticancer Res. 2004 Apr;24(2C):1261–6. 15154657

25. Moreno-Aspitia A, Hillman DW, Dyar SH, Tenner KS, Gralow J, Kaufman PA, et al. Soluble HER2 (sHER2) levels in HER2-positive breast cancer patients receiving chemotherapy ± trastuzumab: Results from the NCCTG adjuvant trial N9831. Cancer. 2013 Aug 1;119(15):2675–82. doi: 10.1002/cncr.28130 23744760

26. Lee HJ, Seo AN, Kim EJ, Jang MH, Suh KJ, Ryu HS, et al. HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer. Am J Clin Pathol. 2014 Dec;142(6):755–66. doi: 10.1309/AJCPIRL4GUVGK3YX 25389328

27. Tchou J, Lam L, Li YR, Edwards C, Ky B, Zhang H. Monitoring serum HER2 levels in breast cancer patients. Springerplus. 2015;4:237. doi: 10.1186/s40064-015-1015-6 26069876

28. Wang T, Zhou J, Zhang S, Bian L, Hu H, Xu C, et al. Meaningful interpretation of serum HER2 ECD levels requires clear patient clinical background, and serves several functions in the efficient management of breast cancer patients. Clin Chim Acta. 2016 Jul 1;458:23–9. doi: 10.1016/j.cca.2016.04.025 27109901

29. Ali SM, Leitzel K, Lipton A, Carney WP, Köstler WJ. Value of serum human epidermal growth factor receptor 2 (HER2)/neu testing for early prediction of response to HER2/neu-directed therapies is still an open one and deserves further study in large prospective trials. J Clin Oncol. 2009 Dec 20;27(36):e273; author reply e274-275. doi: 10.1200/JCO.2009.23.4674 19917836

30. Fornier MN, Seidman AD, Schwartz MK, Ghani F, Thiel R, Norton L, et al. Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate. Ann Oncol. 2005 Feb;16(2):234–9. doi: 10.1093/annonc/mdi059 15668276

31. Lee CK, Davies L, Gebski VJ, Lord SJ, Di Leo A, Johnston S, et al. Serum Human Epidermal Growth Factor 2 Extracellular Domain as a Predictive Biomarker for Lapatinib Treatment Efficacy in Patients With Advanced Breast Cancer. J Clin Oncol. 2016 Mar 20;34(9):936–44. doi: 10.1200/JCO.2015.62.4767 26811533

32. Leary AF, Hanna WM, van de Vijver MJ, Penault-Llorca F, Rüschoff J, Osamura RY, et al. Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer patients. J Clin Oncol. 2009 Apr 1;27(10):1694–705. doi: 10.1200/JCO.2008.17.3989 19255333

33. Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, et al. Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer. J Clin Oncol. 2009 Apr 1;27(10):1685–93. doi: 10.1200/JCO.2008.16.8351 19255335

34. Leyland-Jones B, Smith BR. Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls. Lancet Oncol. 2011 Mar;12(3):286–95. doi: 10.1016/S1470-2045(10)70297-7 21376291

35. Pedersen AC, Sørensen PD, Jacobsen EH, Madsen JS, Brandslund I. Sensitivity of CA 15–3, CEA and serum HER2 in the early detection of recurrence of breast cancer. Clin Chem Lab Med. 2013 Jul;51(7):1511–9. doi: 10.1515/cclm-2012-0488 23403727

36. Mariani L, Miceli R, Michilin S, Gion M. Serial determination of CEA and CA 15.3 in breast cancer follow-up: an assessment of their diagnostic accuracy for the detection of tumour recurrences. Biomarkers. 2009 Mar;14(2):130–6. doi: 10.1080/13547500902770090 19330591

37. Stieber P, Nagel D, Blankenburg I, Heinemann V, Untch M, Bauerfeind I, et al. Diagnostic efficacy of CA 15–3 and CEA in the early detection of metastatic breast cancer-A retrospective analysis of kinetics on 743 breast cancer patients. Clin Chim Acta. 2015 Aug 25;448:228–31. doi: 10.1016/j.cca.2015.06.022 26160053

38. Hayes DF, Zurawski VR, Kufe DW. Comparison of circulating CA15-3 and carcinoembryonic antigen levels in patients with breast cancer. J Clin Oncol. 1986 Oct;4(10):1542–50. doi: 10.1200/JCO.1986.4.10.1542 2428949

39. Tobias R, Rothwell C, Wagner J, et al. Development and Evaluation of a Radioimmunoassay for the Detection of a Monoclonal Antibody Defined Breast Tumor Associated Antigen 115D8/DF3. Clin Chem 1985;31:986.

40. Hilkens J, Buijs F, Hilgers J, Hageman P, Calafat J, Sonnenberg A, et al. Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumors. Int J Cancer. 1984 Aug 15;34(2):197–206. doi: 10.1002/ijc.2910340210 6206003

41. Hilkens J, Hilgers J, Buijs F, et al. Monoclonal Antibodies Against Human Milk-Fat Globule Membranes Useful in Carcinoma Research. Prot Biol Fluids 1984;31:1013–1016.

42. Kufe D, Inghirami G, Abe M, Hayes D, Justi-Wheeler H, Schlom J. Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma. 1984;3(3):223–32. doi: 10.1089/hyb.1984.3.223 6094338

43. Taylor-Papadimitriou J, Gendler S. Molecular Aspects of Mucins. Cancer Rev 1988;11–12:11–24.

44. Fleisher M., Nisselbaum J. S., Loftin L., Smith C., and Schwartz M. K. “Roche RIA and Abbott EIA Carcinoembryonic Antigen Assays Compared.” Clinical Chemistry 30, no. 2 (February 1984): 200–205. 6362912

45. Payne RC, Allard JW, Anderson-Mauser L, et al. Automated assay for HER-2/neu in serum. Clin Chem. 2000;46:175–182. 10657373

46. Luftner D, Cheli C, Mickelson K, Sampson E, Possinger K. ADVIA Centaur HER-2/neu shows value in monitoring patients with metastatic breast cancer. Int J Biol Markers. 2004;19:175–182. 15503818

47. Esteva FJ, Cheli CD, Fritsche H, Fornier M, Slamon D, Thiel RP, et al. Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Cancer Res. 2005;7(4):R436–43. doi: 10.1186/bcr1020 15987448


Článek vyšel v časopise

PLOS One


2020 Číslo 1