Tumour markers in breast cancer - EGTM recommendations

INTRODUCTION

Breast cancer remains one of the main causes of death for women in western countries, with a lifetime risk of developing this malignancy of 12.2% and a lifetime risk of death of 3.6%. Multiple factors are associated with an increase in breast cancer risk. These include genetic and familial factors, hormonal factors (early menarche, late menopause and late first pregnancy), diet, benign breast diseases (mainly associated with atypical hyperplasia) and environmental factors.

The relatively constant mortality, despite increases in incidence, may be the result of improved outcome secondary to earlier detection (screening programs) and advances in treatment. The treatment of primary breast cancer usually includes surgery and/or radiotherapy. Following surgery, there is now increasing use of adjuvant therapies (e.g., either tamoxifen or chemotherapy). The main treatments for distant metastases are chemotherapy, hormone therapy and radiotherapy. About 30-50% of patients with breast cancer relapse within the first ten years after diagnosis. Patients with metastatic breast cancer are incurable using conventional therapy. The proportion of distant metastases is not altered by aggressive local therapies. It is currently believed that many patients presenting with apparently local disease may have micro-metastasis.

Within the past decade, several trials using systemic treatment (chemotherapy or hormone therapy) after primary surgery showed a significant improvement in survival for treated patients compared to controls. In order to rationally administer systemic therapy to patients with local disease, it is necessary to know which patients are at risk of recurrence. The main prognostic factors for both disease free survival (DFS) and overall survival (OS) are nodal involvement, tumour size, lymphatic and vascular invasion, histological grade, nuclear grade and sex steroid receptors. These factors are used to help select patients with aggressive disease who may benefit from adjuvant therapy and to avoid the over-treatment of patients with indolent disease.

TUMOUR MARKERS

Presently, a large number of markers exist for breast cancer. These include MUC-1 (e.g CA15-3), CEA, oncoproteins, milk proteins, and cytokeratins. Of these, CEA and CA15-3 are the most commonly used. Other members of the MUC-1-gene family such as MCA, CA549, BR 27-29 and BRMA have a similar sensitivity and specificity to CA15.3 (1-3). The use of several mucins simultaneously does not provide additional information to that obtained with only one. For this reason, CEA and one mucin are the recommended serum marker in patients with breast cancer. Other markers such as cytokeratins (e.g. TPA, TPS and CYFRA 21.1) and soluble oncoproteins (e.g. c-erbB-2) are promising, but are still under evaluation (1,2).

SERUM TUMOUR MARKERS

Diagnosis

Tumour marker sensitivity in patients with early breast cancer is low (15-35%), and thus markers are not useful for diagnostic purposes (2,4-6). Low levels of markers in patients suspected of having breast cancer does not exclude the presence of malignancy, at either primary or metastatic breast sites. On the other hand, high levels of a marker in patients with breast cancer almost certainly indicate the presence of metastatic disease, i.e. distant metastasis.

Prognosis

Serum levels of CEA, CA15.3 or other MUC-1 products are related to tumour stage, with significantly higher values in patients with nodal involvement than in those without such involvement and in patients with larger tumours (1,2,4,6). Such a relationship with the main prognostic factors suggests a possible prognostic value for these markers. Several studies showed a shorter disease free survival (DFS) and overall survival (OS) in patients with high values of these markers but others report conflicting data (1,2,4-6). It is still not clear if these serum markers are independent prognostic factors. Furthermore, it is not known if the use of tumour markers as indicators of recurrence will lead to improvement in either patient disease-free interval or overall survival. Finally, there is little evidence of a relationship between tumour marker levels and likely response to either chemotherapy or hormone therapy in breast cancer patients.

Follow-up

Serial CEA and CA15.3 serum determinations are useful tools in the early diagnosis of recurrence in patients with breast cancer and no evidence of disease (NED), after radical treatment (1). These tumour markers have been shown to detect 40-60% of relapses before clinical or radiological evidence of disease (e.g. by chest X-ray, liver ultrasonography, bone scans) with a lead-time of between 2 and 18 months (mean 5.2 months) (1-3,11). Tumour marker sensitivity is clearly related to the site of recurrence (1). CEA and CA15.3 are not useful in the early diagnosis of loco-regional recurrence, with clinical examination being the best detection method for these sites. In contrast, abnormal CEA and CA15.3 serum levels are found in 40-50% and 50-70%, respectively, of patients with distant metastases (11,15). Thus, the simultaneous use of both markers allows early diagnosis of metastases in 60-80% of patients with breast cancer. Serial determinations of markers are particularly sensitive for the early detection of bone and liver metastases and the use of markers in these situations may decrease the frequency of both isotope scans and radiological procedures. Chest X-ray should be carried out for detecting lung metastases as markers lack sensitivity for this organ.

The specificity of markers for the detection of recurrences in the follow-up of NED patients is high, but related to the marker cut-off points used (1,2,11,13). In one study, the proportion of false positive results (abnormal values without recurrence) was 5% for CEA and 6.5% for CA 15.3 using cut-off values of 5 m g/L and 35 u/mL, respectively. Using two different criteria, i.e. higher cut-off points (CEA, 10 m g/L: CA15.3 60 u/mL) and confirmation by at least two serial increases (>15%), specificity increased to 99.3% (11). Despite the ability of markers to detect recurrent disease pre-clinically, the long term benefit of early detection on therapy response and patients survival remains to be defined (12).

Therapy monitoring

Tumour marker sensitivity in patients with advanced disease is significantly higher than in loco-regional disease (2,12-23). Likewise, using combinations of several markers (CEA, CA15.3, other MUC-1 products and cytokeratins), it is possible to increase the sensitivity to 95%, especially in patients with distant metastases. The main clinical application of tumour markers in advanced disease is in therapy monitoring. Patients with disease regression usually show decreasing levels while patients with progressive disease generally have increasing levels (1-6). However, whether this monitoring leads to enhanced survival or better quality of life remains to be determined.

TUMOUR MARKERS IN TISSUE

The main tumour markers used in breast cancer tissue are steroid receptors, p53, c-erbB-2, S phase and ploidy. Promising parameters currently being investigated include pS2, urokinase plasminogen activator, PAI-1, cathepsin D, EGFR and topoisomerase (1-3). Steroid receptors are at present the only markers accepted in standard practice. Steroid receptors are not useful in diagnosis, as they may be present in both benign and malignant tissue. On the other hand, steroid receptors have prognostic value in primary and in metastatic breast cancer. Untreated patients with newly diagnosed estrogen receptor (ER)-negative primary breast cancer have higher risk of relapse than ER-positive patients with a similar stage (1-3). On the other hand, the anti-estrogen tamoxifen is more effective in preventing breast cancer recurrences in ER-positive patients than in ER-patients (1,2). Likewise, ER and progesterone receptor (PgR) are useful tools in the selection of therapy in patients with advanced breast cancer. Sixty percent of ER-positive tumours (75% in ER+ PgR+) will respond to hormone therapy in contrast to 15% in the ER-negative group (<10% in ER- , PgR-) (1,31).

p53 and c-erbB-2 are the two oncogene/suppressor genes most studied in breast cancer. Over-expression of the protein products of these genes is found in 35-50% and 20-30% of primary breast cancer, respectively. Over-expression of these oncoproteins is related to more aggressive tumours (high S phase, aneuploidy, higher histological grade, and ER-negativity) but conflicting data exist on their prognostic value (1-6,30,35). Preliminary results suggest that both p53 and c-erbB-2 can predict response to chemotherapy in patients with breast cancer (1,2,3,34,38). However, confirmation of these results in prospective studies is necessary before c-erbB-2 and p53 can enter routine use for predictive purposes.

CONCLUSIONS

MUC-1 antigen and CEA are the most useful serum markers in patients with breast cancer. Serial determinations of these markers are useful in assessing prognosis, early detection of relapse (metastasis) and therapy monitoring. Steroid receptors are the only tissue-based markers accepted in clinical practice, having an established role in predicting hormone-sensitivity and a lesser role in prognosis. Certain new markers such as c-erbB-2, p53 and uPA/PAI-1 look promising as prognostic and predictive factors but further research is necessary before their clinical utility is established.

REFERENCES

  1. Bieglmayer C, Szepesi T, Kopp B, Hoffmann G, Petrik W, Guettuoche K, et al: CA15.3, MCA, CAM26, CAM29 are members of a polymorphic family of mucin-like glycoproteins. Tumor Biol 12: 138-148, 1991.
  2. Dnistrian AM, Schwartz MK, Greenberg EJ, Smith CA, Schwartz DC: Evaluation of CAM26, CAM29, CA15.3 and CEA as circulating tumor markers in breast cancer patients. Tumor Biol 12: 1282-90, 1991.
  3. Price MR, Rye PD, Petrakou R, Murray A, Brady K, Imai S, et al: Summary report on the ISOBM TD-4 workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumor Biol 19 (S1): 1-20, 1998.
  4. Molina R, Jo J, Filella X, Zanon G, Pahisa J, Munoz M, et al: C-erbB-2 oncoprotein, CEA and CA15.3 in patients with breast cancer: prognostic value. Breast Cancer Res Treat 51: 109-119, 1998.
  5. Van Dalen A: Significance of cytokeratin markers TPA, TPA (cyk), TPS and CYFRA 21.1 in metastatic disease. Anticancer Res 16: 2345-2350, 1996.
  6. Gion M, Mione R, Nascimben O, Valsecchi M, Gatti C, Leon A, et al. The tumor associated antigen CA15.3 in primary breast cancer. Evaluation of 667 cases. Br J Cancer 63: 809-813, 1991.
  7. Bast RC, Bates S, Bredt AB, Desch CE, Fritsche H, Fues L, et al: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. J Clin Oncol 14: 2843-2877, 1996.
  8. O’ Hanlon DM, Kerin MJ, Kent P, Maher D, Grimes H, Given HF. An evaluation of preoperative CA15.3 measurement in primary breast carcinoma. Br J Cancer 71:1288-1291, 1995.
  9. Theriault RL, Hortobagyi GN, Fritsche HA, Frye D, Martinez R, Buzdar AU: The role of serum CEA as a prognostic indicator in Stage II and III breast cancer patients treated with adjuvant chemotherapy. Cancer 63: 828-835, 1989.
  10. Van Dalen A: Pre-operative tumour marker levels in patients with breast cancer and their prognosis. Tumor Biol 11: 189-195, 1990.
  11. Molina R, Zanon G, Filella X, Moreno F, Jo J, Daniels M, et al: Use of serial carcinoembryonic antigen and CA15.3 antigen and CA15.3 assays in detecting relapse in breast cancer patients. Breast Cancer Res Treat 36: 41-48, 1995.
  12. Jäger W, Merkle E, Lang N. Increasing serum tumor markers as decision criteria for hormone therapy of metastatic breast cancer. Tumor Biol 12: 60-66, 1994.
  13. Safi F, Kohler I, Rottinger E, Beger HG: The value of the tumor marker CA15.3 in diagnosing and monitoring breast cancer. Cancer 68: 574-582, 1991.
  14. Chang DW, Beveridge RA, Muss H, Fritsche HA, Hortobagyi G, Theriault R, et al: Use of Truquant BR Radioimmunoassay for early detection of breast cancer recurrence in patients with Stage II and Stage III disease. J Clin Oncol 15: 2322-2328, 1997.
  15. Molina R, Jo J, Zanon G, Filella X, Farrus B, Munoz M, et al: Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA15.3. Br J Cancer 74:1126-1131, 1996.
  16. Soletormos G, Nielsen D, Schioler V, Skovsgaard T, Winkel P, Mouridsen HT, et al: A novel method for monitoring high-risk breast cancer with tumor markers: CA15.3 compared to CEA and TPA. Ann Oncol 4: 861-869, 1993.
  17. Loomer L, Brockshmidt JK, Muss HB, Saylor G: Post-operative follow-up of patients with early breast cancer. Patterns of care among clinical oncologists and a review of the literature. Cancer 67: 55-60, 1991.
  18. Soletormos G, Nielsen D, Schioler V, Skovsgaard T, Dombernowsky P: Tumor markers cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen for monitoring metastatic breast cancer during first-line chemotherapy and follow-up. Clin Chem 42: 564-575, 1996.
  19. van Dalen A, Heering KJ, Barak V, Peretz T, Cremaschi A, Geroni P, et al: Treatment response in metastatic breast cancer. A multi-centre study comparing UICC criteria and tumour marker changes. Breast 5: 82-88, 1996.
  20. Robertson JFR, Pearson D, Price MR, Selby C, Blamey RW, Howell A. Objective measurement of therapeutic response in breast cancer using tumour markers. Br J Cancer 64: 757-763, 1991.
  21. Tondini C, Hayes DF, Gelman R, Henderson IC, Kufe DW: Comparison of CA15.3 and carcinoembryonic antigen in monitoring the clinical course of patients with metastatic breast cancer. Cancer Res 48: 4107-4112, 1988.
  22. Williams MR, Turkes A, Pearson D, Twining P, Griffiths K, Blamey RW: The use of serum carcinoembryonic antigen to assess therapeutic response in locally advanced and metastatic breast cancer. A prospective study with external review. Eur J Surg Oncol 14: 417-422, 1988.
  23. Palazzo S, Liguori V, Molinari B: Is the carcinoembryonic antigen test a valid predictor of response to medical therapy in disseminated breast cancer? Tumori 72: 515-518, 1986.
  24. Foekens JA, van Putten WLJ, Portengen H, Dekoning HYWCM, Thirion B, Alexieva-Figusch J, et al: Prognostic value of pS2 and cathepsin D in 710 human primary breast tumors: Multivariate analysis. J Clin Oncol 11: 899-908, 1993.
  25. Spyratos F, Martin PM, Hacene K, Romain S, Andrieu C, Ferreropous M, et al: Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Nat Cancer Inst 84:1266-1272, 1992.
  26. Janicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Hofler H, et al: Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24: 195-209, 1993.
  27. Pichon MF, Pallud C, Hacene K, Milgrom E: Prognostic value of progesterone receptor after long-term follow-up in primary breast cancer. Eur J Cancer 28A:1676-1680, 1992.
  28. Ewers SB, Attewell R, Baldetorp B, Borg A, Ferno M, Langstrom E, et al: Prognostic significance of flow cytometric DNA analysis and estrogen receptor content in breast carcinomas. A 10 year survival study. Breast Cancer Res Treat 24: 115-126, 1992.
  29. Elledge RM, McGuire WL, Osborn CK: Prognostic factors in breast cancer. Semin Oncol 19: 244-253, 1992.
  30. Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. Lancet 339: 71-85, 1992.
  31. Steward HJ, for the Scottish Cancer Trials Breast Group: The Scottish trial of adjuvant tamoxifen in node-negative breast cancer. J Nat Cancer Inst Monograph 11: 117-120, 1992.
  32. Ravdin PM, Green S, Dorr TM, McGuire WL, Fabian C, Pugh RP, et al. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: Results of a prospective Southwest Oncology Group study. J Clin Oncol 10: 1284-1291, 1992.
  33. Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, et al: Over-expression of HER-2/neu and its relationship with other prognostic factors change during the progression of in-situ to invasive breast cancer. Human Pathol 23: 974-979, 1992.
  34. Allred DC, Clark GM, Tandon AK, Molina R, Tormey DC, Osborne CK, et al: HER-2/neu in node-negative breast cancer: Prognostic significance of over expression influenced by the presence of in situ carcinoma. J Clin Oncology 10: 599-605, 1992.
  35. Thor AD, Moore DH, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, et al: Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancer. J Nat Cancer Inst 84: 845-854, 1992.
  36. Allred DC, Clark GM, Elledge R, et al: Accumulation of mutant p53 is associated with increased proliferation and poor clinical outcome in node-negative breast cancer. J Nat Cancer Inst 85: 176-177, 1993.
  37. Silvestrini R, Veronesi S, Benini E, et al: Expression of p53, glutathione S-transferase pi and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer. J Nat Cancer Inst 89: 639-645, 1997.
  38. Clark GM, Dressler LG, Owens MA, Pounds G, Oldaker T, McGuire WL: Prediction of relapse or survival in patients with node-negative breast cancer by DNA flow cytometry. N Engl J Med 320: 627-633, 1989.
  39. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, et al: C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. New Engl J Med 330:1260-1266, 1994.
  40. Leitzel K, Teramoto Y, Konrad K, Chinchilli VM, Volas G, Grossberg H, et al: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13: 1129-1135, 1995.
  41. Wright C, Cairns J, Cantwell BJ, Cattan AR, Hall AG, Harris AL, et al: Response to mitoxantrone in advanced breast cancer. Correlation with expression of c-erbB-2 protein and glutathione S-transferases. Br J Cancer 65: 271-274, 1992.

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