1. Chapter 19 Tumor Markers Zou Xiong

2. DEFINITIONS-1 Tumor markers originally were defined as substances that can be measured quantitatively by immunochemical means in tissue or body fluids to identify the presence of a cancer and possibly the organ where it resides, to establish the extent of tumor burden before treatment, to predict prognosis, and to monitor the response to therapy.

3. DEFINITIONS-2 tumor markers tumor-associated antigens nuclear and specific proteins enzymes isoenzymes genes oncogenes and their products

4. DEFINITIONS-3 Epidemiological sensitivity is the percentage of true positives. Specificity is the percentage of true normals. The positive predictive value is a percentage of the true positives compared to positive values. The negative predictive value is the true negatives compared to all negatives. The efficiency of the test is the true negatives and true positives divided by the number of tested individuals.

5. DEFINITIONS-4 Analytical sensitivity can be defined as the lowest detectable amount of marker measured by the method in use, while Analytical specificity reflects the extent of exogenous material interferences in the assay.

6. APPLICATION 1.Carcinoembryonic Antigen (CEA)

7. APPLICATION-1 When first described, CEA apparently was elevated in almost all patients with colorectal cancer, but was normal after successful removal of the tumor. 30 years later, it now is well-understood that CEA is elevated in all solid-tissue tumors, not only those of the colon or rectum and is elevated in the cancer of the breast, ovary, and pancreas.

8. APPLICATION-2 Following successful therapy, elevations of CEA may fall and subsequent elevations suggest recurrence. These elevations may be seen months, if not years, before there is clinical evidence of disease. It is important to understand that elevations will not be seen in about 30% of individuals with recurrent metastasis disease.

9. APPLICATION-3 American Society of Clinical Oncology (ASCO) concluded that CEA cannot be used for screening for colon-rectal cancer, but preoperative CEA may assist staging and surgical treatment planning. CEA elevations detect recurrence earlier than other techniques and CEA monitoring should be done at the start of treatment and then every 2 to 3 months thereafter.

10. 2. CA19-9

11. APPLICATION CA19-9 is the marker most useful in adenocarcinoma of the pancreas. It is more sensitive (70% to 95%) and specific (72%) than CEA (40% to 60% and 70% respectively). CA19-9 is not elevated in islet cell carcinoma of the pancreas. Benign conditions such as acute or chronic pancreatitis or cholelithiasis may cause elevations.

12. 3. CA72-4

13. APPLICATION CA72-4 elevated in patients with many different gastrointestinal cancers and only rarely in benign gastrointestinal diseases. It is more sensitive and specific than any other marker in gastric cancer. It identified 59% of the patients compared to 52% with CA19-9 and 25% with CEA. When combined with CA19-9, 70% of the gastric cancer patients were identified.

14. 4. Alpha Feto Protein (AFP)

15. APPLICATION AFP has been used for more than 30 years in screening for hepatocellular cancer (HCC) and in diagnosis and monitoring of patients with germ-cell tumors. AFP screening is not useful in detecting cirrhotic patients who will develop HCC. AFP is of use in monitoring patients with HCC. The concentrations rise and fall, reflecting the course of the disease, and may be reflective of recurrence before any other clinical or diagnostic indication.

16. 5.Human Chorionic Gonadotropin (hCG) and its BetaSubunit (β-hCG)

17. APPLICATION hCG and β-hCG has been used for more than 50 years in the diagnosis and monitoring of trophoblastic cancers such as choriocarcinoma and hydatidiform mole. AFP and β-hCG have been used to predict therapeutic response and to evaluate prognosis of testicular cancer.

18. 6. CA-125

19. APPLICATION-1 CA-125 has been observed in the patients with ovarian cancer but also is elevated in a variety of cancers (uterus, pancreas, liver, lung). Elevations of CA-125 may be seen in many nonmalignant conditions including pregnancy, menstruation, ovarian cysts, endometriosis, and peritoneal or pleural inflammation. CA-125 cannot be used for early diagnosis.

20. APPLICATION-2 CA-125 is an important marker because elevations after treatment suggest presence of residual tumor, and second-look exploratory surgery probably is unwarranted. CA-125 may be a prognostic predictor. U se of an algorithm and sequential CA-125 results may make it possible to use CA-125 for early detection ( sensitivity 83%, specificity 99.8%, and positive predictive value 16%).

21. 7.Prostate-Specific Antigen (PSA)

22. APPLICATION-1 PSA is prostate tissue specific but not prostate cancer specific. Elevations (PSA >4.0 μg /L) are seen in about 40% of men with early prostate cancer, 70% of men with more advanced cancer, and in 20% of men with benign prostatic hypertrophy (BPH). After surgical removal of the prostate, the PSA in serum falls with a half-life of 3.2 ± 0.6 days.A subsequent elevation to very low levels suggests recurrence.

23. APPLICATION-2 Preoperative PSA values may be important prognostic markers. The FDA recently has approved the use of PSA for screening. 60% to 70% of men with PSA values > 10 μg /L will have biopsy-proven cancer.

24. 8.Free and Complexed PSA

25. APPLICATION-1  PSA exists in serum primarily as three forms. One form is complexed to the protease inhibitor α1- antichymotrypsin, A second is complexed to α-2 macroglobulin The remainder is noncomplexed (free PSA).  The total PSA is presumably the free and the antichymotrypsin bound form because the α-2 macroglobulin form is not immunoreactive.

26. APPLICATION-2 If the ratio between free and total PSA was greater than 0.154, benign disease was present, and if it was lower, the patient suffered from cancer. With this cut-off, 93% of men with BPH were identified.

27. 9. Acid Phosphatase

28. APPLICATION Acid phosphatase is one of the oldest cancer markers and has been used for more than 50 years in monitoring patients with prostate cancer. Elevations are seen in about 80% of men with bone metastases but in 20% or less of men with localized cancer. PSA is more sensitive and more useful than acid phosphatase and will be elevated in patients with smaller tumors.

29. 10. Breast Antigen (CA15-3)

30. APPLICATION-1  Elevations are directly related to stage. In one study of CA15-3 elevation, * 9% of women with stage I disease * 19% of those with stage II disease * 38% in women with stage III cancer * 75% with stage IV.

31. APPLICATION-2 The ASCO panel, recommended hormone receptor assays be used in management, but concluded that present data are insufficient to recommend CA15-3 for screening, diagnosis, staging, or surveillance following primary treatment. CA15-3 is not useful in screening because its presence in the serum is related to the extent of tumor burden and the stage of the cancer nor is it useful prognostic marker.

32. 11. HER-2/neu

33. APPLICATION-1 The neu oncogene in rats was reported to encode an epidermal growth factor receptor-related protein with a molecular weight of 185Kd (p185). The human homologue of the rat neu oncogene has been referred to as C-erb-B-2 or HER-2/neu. The HER-2/neu gene is amplified in a variety of epithelial-cell tumors. Most attention has been paid to this amplification in breast cancer and the increases in the protein product.

34. APPLICATION-2 Breast cancer patients with HER-2/neu positive primary tumors have a poor prognosis with shorter disease free and overall survival. Many reports suggest that patients with HER-2/neu- positive primary tumors should be monitored for elevated serum HER-2/neu levels as a means of detecting early recurrence. Elevated levels of serum HER-2/neu correlate with the presence of metastatic disease and poor prognosis and may be valuable in predicting response to various forms of therapy.

35. APPLICATION-3  In normal women the specificity of HER-2/neu was 100% and those with benign disease was 95%.  In women with breast cancer, the sensitivity was * 1.7% in stage I disease, * 3.0% in stage II disease * 35.5% in stage V.  A combination of serum HER-2/neu, CA15-3 and CEA allowed a more precise evaluation of response to therapy

36. APPLICATION-4 Serum concentrations were correlated to tumor size and node involvement. Elevated HER-2/neu levels indicated a lack of response to hormonal therapy. Serum HER-2/neu levels before chemotherapy were found to correlate with the number of positive nodes, but there was no correlation to age, receptor, or disease status.

37. 12. Enzymes as Tumor Markers

38. APPLICATION Many of the markers already discussed are enzymes (acid phophatase, prostate specific antigen). However, many other enzymes are valid markers, some of which have been used for decades and are still of clinical relevance.

39. 13. Alkaline Phosphatase (ALP)

40. APPLICATION-1 Serum ALP is elevated in patients with primary bone cancer as well as in individuals with cancer metastatic to bone. Elevations are greater in persons with osteoblastic bone lesions than in patients with osteolytic disease. In osteoblastic disease, serum levels can be as much as 40-fold the upper reference level. Because the majority of metastatic bone lesions in breast cancer are osteolytic and in prostate cancer osteoblastic, elevations of ALP in prostate cancer usually are much higher than in breast cancer.

41. APPLICATION-2 Serum levels reflect regression and progression, but there may be a paradoxical rise in ALP during the early phase of disease regression, presumably reflecting an attempt to repair the damaged bone. Alkaline phosphatase exists in forms that are organ related; primarily bone, liver, and placenta. The bone-ALP measured immunochemically with monoclonal antibodies has been successfully used to monitor metastases to bone and differentiate bone verses liver-elevated serum ALP levels.

42. 14. Lactate Dehydrogenase (LDH)

43. APPLICATION The role of LDH in algorithms already has been discussed. Serum levels of total LDH have been found useful in hematologic cancers. Patients with lymphoma have been stratified based on LDH levels and remission rates are related to this level.

44. 15. Neuron-Specific Enolase (NSE)

45. APPLICATION-1 Enolase exists as three dimeric subunits γ, β, α, which give rise to five isoenzymes: αα, ββ, γγ, αβ, and αγ. The γγ isomer (NSE) is the predominant form in brain. In serum, it is a specific marker for the family or neuroendocrine tumors referred to as the amine precursor uptake decarboxylase (APUD) tumors including neuroblastoma, medullary carcinoma of the thyroid, and small-cell carcinoma of the lung (SCCL).

46. APPLICATION-2 Elevations initially were observed in 90% of patients with neuroblastoma, primarily those with extensive disease, and in 70% of patients with SCCL. NSE is useful in monitoring patients. Falls reflect response to successful therapy and subsequent elevations reflect an exacerbation.

47. CONCLUSION-1 Circulating and tissue-tumor markers have been proposed as clinically useful in screening, diagnosis, prediction of prognosis, and patient management.

48. CONCLUSION-2 In screening, the marker should merely answer the question as to whether a cancer is present or not. In diagnosis, the markers should aid in confirmation of the cancer and also provide information on how severe or extensive the malignancy is (staging). In prognosis, the marker should assist in predicting the aggressiveness of the tumor.

49. CONCLUSION-3 The most significant and accepted use of markers is in assistance in the therapeutic management of the cancer patient. In this case, there are two questions the marker can help to answer: ⑴ what is the prognosis before therapeutic intervention; ⑵ what is the probability of success of specific therapy.

50. CONCLUSION-4 Marker levels may suggest a need for a change in therapy or for additional therapy and provide lead- time for initiation of new or more aggressive therapy. It must be emphasized that markers may not be elevated in some patients with extensive and progressive tumors. The important point is that a positive marker may be very meaningful from a clinical point of view, but a negative marker should never create a false sense of security that tumor is not present or is not progressing.

51. CONCLUSION-5 Although tumor markers can provide information on regression or progression of disease, the question arises whether the costs of the assay, and more importantly, the cost of other diagnostic procedures triggered by positive marker results, are justifiable in the treatment of ultimately incurable disease and what level of intervention is acceptable among false positives. The acceptance or rejection of these costs is related to the individual ’ s definition of cost effectiveness.

52. CONCLUSION AFPCA125CA153CA199CA72-4CEA CYFRA 21-1 HCGNSE Free PSA Total PSA cholangiocarcinoma ★ breast carcinoma ★★ Islet cell carcinoma ★ uterine cervix cancer ★ chorionic carcinoma ★ intestinal carcinoma ★★ esophageal carcinoma ★ germinocarcinoma ★★ hepatoma ★ SCLC ★ NSCLC ★★ ovarian cancer ★★ pancreatic carcinoma ★★ prostatic carcinoma ★★ gastric carcinoma ★★★