Re:암 표지자(Tumor markers) 에 대하여

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Tumor Markers

What are tumor markers?

Tumor markers are substances that are produced by cancer or by other cells of the body in response to cancer or certain benign (noncancerous) conditions. Most tumor markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumor tissue, or other tissues or bodily fluids of some patients with cancer. Most tumor markers are proteins. However, more recently, patterns of gene expression‎ and changes to DNA have also begun to be used as tumor markers.

튜머 마커란 암에 의해서 혹은 암이나 양성 종양에 반응하는 신체의 다른 세포에서 생산된 물질이다. 대부분의 듀머 마커는 암세포 뿐 아니라 정상 세포에 의해서도 생산된다. 그러나, 암 상황에서는 훨씬 많이 생산된다. 이러한 마커들은 혈액, 소변, 대변, 종양 조직 혹은 몇몇 암 환자의 다른 조직 혹은 체액에서 발견된다. 대부분 튜머마커는 단백질이다. 그러나 최신에는 유전 발현 패턴과 DNA의 변화도 튜머 마커로써 사용된다.

Many different tumor markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. No “universal” tumor marker that can detect any type of cancer has been found.

어떤 마커는 한개의 암과 연관되지만 다른 마커는 두개 혹은 그 이상 암 유형과 연관 된다. 지금까지 발견된 어떤 종류의 암을 발견할 수 있는 "보편적인" 튜머 마커는 없다.

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumor marker associated with that cancer. Moreover, tumor markers have not been identified for every type of cancer.

간혹 암이 아닌 상황에서도 뚜렷한 증가가 나타나는 겨우도 있고, 특이 암에 높아져야할 튜머 마커가 반드시 올라가는 것도 아니다. 또한, 모든 종류의 암에 튜머 마커가 있는 건 아니다.

How are tumor markers used in cancer care?

Tumor markers are used to help detect, diagnose, and manage some types of cancer. Although an elevated level of a tumor marker may suggest the presence of cancer, this alone is not enough to diagnose cancer. Therefore, measurements of tumor markers are usually combined with other tests, such as biopsies, to diagnose cancer.

튜머 마커는 발견, 진단, 몇몇 암에서는 관리를 위해 사용된다. 단독으로 사용된다기 보단 생검이나 다른 검사와 혼합하여 사용된다.

Tumor marker levels may be measured before treatment to help doctors plan the appropriate therapy. In some types of cancer, the level of a tumor marker reflects the stage (extent) of the disease and/or the patient’s prognosis (likely outcome or course of disease). More information about staging is available in the NCI fact sheet Cancer Staging.

적절한 치료 계획을 세우는데 도움을 준다. 어떤 암에서는 질병의 단계나 환자의 예후를 반영하기도 한다.

Tumor markers may also be measured periodically during cancer therapy. A decrease in the level of a tumor marker or a return to the marker’s normal level may indicate that the cancer is responding to treatment, whereas no change or an increase may indicate that the cancer is not responding.

암치료 동안 주기적의 측정되기도 한다. 치료에 잘 반응하지는지를 체크하기 위함.

Tumor markers may also be measured after treatment has ended to check for recurrence (the return of cancer).

치료 후 재발 체크를 위해 측정되기도 한다.

How are tumor markers measured? 

A doctor takes a sample of tumor tissue or bodily fluid and sends it to a laboratory, where various methods are used to measure the level of the tumor marker.

If the tumor marker is being used to determine whether treatment is working or whether there is a recurrence, the marker’s level will be measured in multiple samples taken over time. Usually these “serial measurements,” which show whether the level of a marker is increasing, staying the same, or decreasing, are more meaningful than a single measurement.

혈액이나 체액으로 검사한다. 

만약 튜머 마커가 치료가 작용하는지 아닌지, 재발이 있는지 없는지 결정하는데 사용된다면, 마커의 level을 추가로 여러 샘플로 측정될 것이다. 보통 이러한 "시러얼 측정"은 마커가 증가하는지, 같은 수준으로 머무는지, 혹은 감소하는 지를 보여주고 단순 측정보다 더욱 의미를 갖는다.

Does NCI have guidelines for the use of tumor markers? 

NCI does not have such guidelines. However, some national and international organizations do have guidelines for the use of tumor markers for some types of cancer:

NCI에 가이드라인은 없다. 아래 조직에 튜머마커에 대한 가이드라인이 있다.

·         The American Society of Clinical Oncology (ASCO) has published clinical practice guidelinesExit Disclaimer on a variety of topics, including tumor markers for breast cancer, colorectal cancer, lung cancer, and others.

·         The National Academy of Clinical Biochemistry publishes laboratory medicine practice guidelines, including Use of Tumor Markers in Clinical Practice: Quality RequirementsExit Disclaimer, which focuses on the appropriate use of tumor markers for specific cancers.

What tumor markers are currently being used, and for which cancer types?

A number of tumor markers are currently being used for a wide range of cancer types. Although most of these can be tested in laboratories that meet standards set by the Clinical Laboratory Improvement Amendments, some cannot be and may therefore be considered experimental. Tumor markers that are currently in common use are listed below.

ALK gene rearrangements and overexpression‎

·         Cancer types: Non-small cell lung cancer and anaplastic large cell lymphoma

·         Tissue analyzed: Tumor

·         How used: To help determine treatment and prognosis

Alpha-fetoprotein (AFP)

·         Cancer types: Liver cancer and germ cell tumors

·         Tissue analyzed: Blood

·         How used: To help diagnose liver cancer and follow response to treatment; to assess stage, prognosis, and response to treatment of germ cell tumors

Beta-2-microglobulin (B2M)

·         Cancer types: Multiple myeloma, chronic lymphocytic leukemia, and some lymphomas

·         Tissue analyzed: Blood, urine, or cerebrospinal fluid

·         How used: To determine prognosis and follow response to treatment

Beta-human chorionic gonadotropin (Beta-hCG)

·         Cancer types: Choriocarcinoma and germ cell tumors

·         Tissue analyzed: Urine or blood

·         How used: To assess stage, prognosis, and response to treatment

BRCA1 and BRCA2 gene mutations

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

BCR-ABL fusion gene (Philadelphia chromosome)

·         Cancer type: Chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myelogenous leukemia

·         Tissue analyzed: Blood and/or bone marrow

·         How used: To confirm‎ diagnosis, predict response to targeted therapy, and monitor disease status

BRAF V600 mutations

·         Cancer types: Cutaneous melanoma and colorectal cancer

·         Tissue analyzed: Tumor

·         How used: To select patients who are most likely to benefit from treatment with certain targeted therapies

C-kit/CD117

·         Cancer types: Gastrointestinal stromal tumor and mucosal melanoma

·         Tissue analyzed: Tumor

·         How used: To help in diagnosing and determining treatment

CA15-3/CA27.29

·         Cancer type: Breast cancer

·         Tissue analyzed: Blood

·         How used: To assess whether treatment is working or disease has recurred

CA19-9

·         Cancer types: Pancreatic cancer, gallbladder cancer, bile duct cancer, and gastric cancer

·         Tissue analyzed: Blood

·         How used: To assess whether treatment is working

CA-125

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assessment of response to treatment, and eval‎uation ofrecurrence

Calcitonin

·         Cancer type: Medullary thyroid cancer

·         Tissue analyzed: Blood

·         How used: To aid in diagnosis, check whether treatment is working, and assess recurrence

Carcinoembryonic antigen (CEA)

·         Cancer types: Colorectal cancer and some other cancers

·         Tissue analyzed: Blood

·         How used: To keep track of how well cancer treatments are working or check if cancer has come back

CD20

·         Cancer type: Non-Hodgkin lymphoma

·         Tissue analyzed: Blood

·         How used: To determine whether treatment with a targeted therapy is appropriate

Chromogranin A (CgA)

·         Cancer type: Neuroendocrine tumors

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assessment of treatment response, and eval‎uation of recurrence

Chromosomes 3, 7, 17, and 9p21

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To help in monitoring for tumor recurrence

Circulating tumor cells of epithelial origin (CELLSEARCH?)

·         Cancer types: Metastatic breast, prostate, and colorectal cancers

·         Tissue analyzed: Blood

·         How used: To inform clinical decision making, and to assess prognosis

Cytokeratin fragment 21-1

·         Cancer type: Lung cancer

·         Tissue analyzed: Blood

·         How used: To help in monitoring for recurrence

EGFR gene mutation analysis

·         Cancer type: Non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To help determine treatment and prognosis

Estrogen receptor (ER)/progesterone receptor (PR)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with hormone therapy and some targeted therapies is appropriate

Fibrin/fibrinogen

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To monitor progression and response to treatment

HE4

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To plan cancer treatment, assess disease progression, and monitor for recurrence

HER2/neu gene amplification or protein overexpression‎

·         Cancer types: Breast cancer, gastric cancer, and gastroesophageal junction adenocarcinoma

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with certain targeted therapies is appropriate

Immunoglobulins

·         Cancer types: Multiple myeloma and Waldenström macroglobulinemia

·         Tissue analyzed: Blood and urine

·         How used: To help diagnose disease, assess response to treatment, and look for recurrence

KRAS gene mutation analysis

·         Cancer types: Colorectal cancer and non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

Lactate dehydrogenase

·         Cancer types: Germ cell tumors, lymphoma, leukemia, melanoma, and neuroblastoma

·         Tissue analyzed: Blood

·         How used: To assess stage, prognosis, and response to treatment

Neuron-specific enolase (NSE)

·         Cancer types: Small cell lung cancer and neuroblastoma

·         Tissue analyzed: Blood

·         How used: To help in diagnosis and to assess response to treatment

Nuclear matrix protein 22

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To monitor response to treatment

Programmed death ligand 1 (PD-L1)

·         Cancer type: Non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

Prostate-specific antigen (PSA)

·         Cancer type: Prostate cancer

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assess response to treatment, and look for recurrence

Thyroglobulin

·         Cancer type: Thyroid cancer

·         Tissue analyzed: Blood

·         How used: To eval‎uate response to treatment and look for recurrence

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To determine aggressiveness of cancer and guide treatment

5-Protein signature (OVA1?)

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To pre-operatively assess pelvic mass for suspected ovarian cancer

21-Gene signature (Oncotype DX?)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To eval‎uate risk of recurrence

70-Gene signature (Mammaprint?)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To eval‎uate risk of recurrence

Can tumor markers be used in cancer screening? 

Because tumor markers can be used to assess the response of a tumor to treatment and for prognosis, researchers have hoped that they might also be useful in screening tests that aim to detect cancer early, before there are any symptoms. For a screening test to be useful, it should have very high sensitivity (ability to correctly identify people who have the disease) and specificity (ability to correctly identify people who do not have the disease). If a test is highly sensitive, it will identify most people with the disease—that is, it will result in very few false-negative results. If a test is highly specific, only a small number of people will test positive for the disease who do not have it—in other words, it will result in very few false-positive results.

튜머 마커는 치료에 반응하는 지 혹은 예후를 평가하는데 사용될 수 있기 때문에, 연구자들은 암을 증상이 나타나기 전에 조기 발견하는 목적으로 스크리닝 테스트가 유용하기를 희망한다. 스크리닝 테스트가 유용하기 위해서는 매우 높은 민감도와 특이도가 있으어 한다. 

Although tumor markers are extremely useful in determining whether a tumor is responding to treatment or assessing whether it has recurred, no tumor marker identified to date is sufficiently sensitive or specific to be used on its own to screen for cancer.

비록 튜머 마커는 튜머가 치료에 반응하는지, 재발이 있는지 없는 지 결정하는데는 매우 유용하지만, 민감도 특이도에 대한 자료는 충분치 않다.

For example, the prostate-specific antigen (PSA) test, which measures the level of PSA in the blood, is often used to screen men for prostate cancer. However, an increased PSA level can be caused by benign prostate conditions as well as by prostate cancer, and most men with an elevated PSA level do not have prostate cancer. Initial results from two large randomizedcontrolled trials, the NCI-sponsored Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the European Randomized Study of Screening for Prostate Cancer, showed that PSA testing at best leads to only a small reduction in the number of prostate cancer deaths. Moreover, it is not clear whether the benefits of PSA screening outweigh the harms of follow-up diagnostic tests and treatments for cancers that in many cases would never have threatened a man’s life.

예를 들면, PSA검사는 종종 전립선암을 스크리닝 하는데 사용된다. 그러나 증가된 PSA는 양성 전립선 종양에서도 높아질 수 있고, 증가된 PSA를 갖은 사람이 암이 없는경우가 대부분이다.

Similarly, results from the PLCO trial showed that CA-125, a tumor marker that is sometimes elevated in the blood of women with ovarian cancer but can also be elevated in women with benign conditions, is not sufficiently sensitive or specific to be used together with transvaginal ultrasound to screen for ovarian cancer in women at average risk of the disease. An analysis of 28 potential markers for ovarian cancer in blood from women who later went on to develop ovarian cancer found that none of these markers performed even as well as CA-125 at detecting the disease in women at average risk.

CA-125도 난소암에서 혈중 level이 높아지지만 양성 종양에도 반응하고 민감도 특이도가 충분치 않아 질초음파와 함깨 사용한다.  

What kind of research is under way to develop more accurate tumor markers? 

Cancer researchers are turning to proteomics (the study of protein structure, function, and patterns of expression‎) in hopes of developing new biomarkers that can be used to identify disease in its early stages, to predict the effectiveness of treatment, or to predict the chance of cancer recurrence after treatment has ended.

암 연구가들은 프로테오믹스(단백질 구조, 기능, 발현 패턴)로 방향을 돌리고 있다. 

Scientists are also eval‎uating patterns of gene expression‎ for their ability to help determine a patient’s prognosis or response to therapy. 

과학자들은 또한 유전자 발현의 패턴을 평가한다. 

For example, results of the NCI-sponsored TrialAssigning IndividuaLized Options for Treatment (Rx), or TAILORx , showed that for women recently diagnosed with lymph node–negative, hormone receptor–positive, HER2-negative breast cancer who had undergone surgery, those with the lowest 21-gene (Oncotype Dx?) recurrence scores had very low recurrence rates when given hormone therapy alone and thus can be spared chemotherapy. The trial is ongoing to see whether women at intermediate risk of recurrence, based on the 21-gene test, do better with chemotherapy in addition to hormone therapy than with hormone therapy alone.

림프 노드 negative, 호르몬 리셉터 positive, HER2 negative인 유방암으로 진단되어 수술을 시행한 환자에게, 낮은 21-유전자 재발 점수는 호르몬 치료 단독으로 받을 때, 매우 낮은 재발률을 갖는다. 그 결과 화학치료로 해를 입지 않을 수 있다.   

More information on NCI’s role in supporting research on novel tools and methods for diagnosing cancer is available on the Diagnosis research page.

Selected References

1.      Bigbee W, Herberman RB. Tumor markers and immunodiagnosis. In: Bast RC Jr., Kufe DW, Pollock RE, et al., editors. Cancer Medicine. 6^th ed. Hamilton, Ontario, Canada: BC Decker Inc., 2003.

2.      Andriole G, Crawford E, Grubb R, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine 2009; 360(13):1310–1319. [PubMed Abstract]

3.      Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine 2009; 360(13):1320–1328.[PubMed Abstract]

4.      Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial.JAMA 2011; 305(22):2295–2303. [PubMed Abstract]

5.      Cramer DW, Bast RC Jr, Berg CD, et al. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prevention Research 2011; 4(3):365–374. [PubMed Abstract]

6.      Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression‎ assay in breast cancer. New England Journal of Medicine 2015; First published online September 28, 2015. doi: 10.1056/NEJMoa1510764Exit Disclaimer.

Related Resources

·         Cancer Staging

·         Prostate-Specific Antigen (PSA) Test

·         Targeted Cancer Therapies

·         Understanding Cancer Prognosis

·         Understanding Laboratory Tests

·         Reviewed: November 4, 2015

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