Tumor Markers Yesterday, Today & Tomorrow Steven E. Zimmerman M.D. Vice President & Chief Medical Director
Tumor Marker - Definition Substances produced by cancer cells or other cells in response to cancer or certain benign conditions Most are made by normal cells as well as cancer cells Can be found in blood, urine, stool, tumor tissue, or other tissues or bodily fluids Most are proteins, but more recently patterns of gene expression and changes to DNA have been used 2
How are tumor markers used? Screening and early detection of cancer Diagnosing cancer Determining prognosis for certain cancers Determining if certain treatments are likely to work Determining how well treatment is working Looking for recurrent cancer 3
SCREENING 4
Principles of Cancer Screening Likelihood of test correctly identifying cancer: Sensitivity number of cancers missed Specificity number of cancers inappropriately diagnosed Likelihood of cancer being present Harm from follow-up procedures Suitable treatment available & appropriate Does early detection improve outcomes Lead-time bias Will cancer ever need treatment The extent to which the cancer is treatable 5
Cancers Where Screening May Useful Breast Cancer Cervical Cancer Lower GI Cancer Prostate Cancer Lung Cancer Oral Cancer Skin Cancer 6
Cancers Where Screening May Useful Breast Cancer Cervical Cancer Lower GI Cancer Prostate Cancer Lung Cancer Oral Cancer Skin Cancer Of all these cancers, only prostate cancer has a tumor marker that has efficacy as a screening test 7
Relationship of Incidence of Prostate Cancer to PSA Testing PSA testing rates increased from 1.2% in 1988 to 40% in 1994 Percent of Caucasian males with 1 st PSA peaked at 19% in 1992, and subsequently declined
Estimated Probability of Prostate Cancer with Normal DRE Barry M. N Engl J Med 2001;344:1373-1377
PSA Possible Improvements Age-specific Reference Ranges (lower cut-off values) Age 40 49 2.5 ng/ml Age 50 59 3.5 ng/ml Age 60 69 4.5 ng/ml Age 70 79 6.5 ng/ml PSA velocity > 0.75 ng/ml/yr Free-PSA ratio (free PSA/total PSA) in percentage PSA between 4.0 ng/ml and 10.0 mg/ml & normal DRE Free-PSA% < 10% up to 56% with cancer Free PSA% > 25% 8% with cancer
Prostate Cancer Antigen 3 (PCA3) Gene only expressed in human prostate tissue, and highly overexpressed in prostate cancer Compared with PSA: Lower sensitivity, higher specificity Better positive and negative predictive value Useful in predicting presence of prostate cancer in men undergoing repeat prostate biopsy Assay is ratio of PCA3 RNA to PSA RNA in post-digital rectal exam first voided urine PCA3 score <25 associated with decrease likelihood of positive biopsy 11
Incidence of and Mortality from Prostate Cancer in the United States, 1987 through 1997 Barry M. N Engl J Med 2001;344:1373-1377
Question: For asymptomatic men in the general population, do the benefits of PSA testing for prostate cancer screening outweigh the potential harms? 13
Benefits of PSA Screening Although screening leads to more prostate cancer diagnosis, no statistically significant differences in overall or prostate cancer-specific mortality has been demonstrated European Randomised Study of Screening for Prostate Cancer (ERSPC) 11 year follow-up 162,388 men between 55 and 69 years of age 20% reduction in prostate cancer-specific mortality for men in the screening arm 14
Harms with PSA Screening Harms associated with diagnostic evaluation included infection, bleeding and urinary difficulties Two population-based studies reported an increase over time in the 30 day hospitalization rate for infection-related causes False positive rate was 12.5 13% 15
Conclusions It is uncertain whether the benefits associated with PSA screening are worth the harms associated with screening and subsequent unnecessary treatment Because the evidence does not clearly inform the issue around PSA testing and its downstream effects, the importance of informed and shared decision-making becomes paramount 16
Prostate Cancer Screening in Average and High Risk Men: ACS (2010); USPSTF (2012) Recommendation ACS USPSTF PSA Testing The ACS recommends that asymptomatic men who have at least a 10-year life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer, after receiving information about the uncertainties, risks, and potential benefits associated with prostate cancer screening. The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for prostate cancer. This is a grade D recommendation.
CEA as a Screening Test CEA described in 1965, present in both fetal colon and colon adenocarcinoma Normal limits: 2.5 ng/ml nonsmokers 5.0 ng/ml smokers Elevated CEA for nonmalignant disorders peptic ulcer, pancreatitis, diverticulitis, inflammatory bowel disease
CEA as a Screening Test cont. Most elevations are in the 2.5 ng/ml to 10.0 ng/ml range majority no cause found Few will have undetected malignancy majority of these will be colorectal cancers < 25% with tumors confined to colon will have elevations Sensitivity increases with advancing tumor stage 50% with tumor extension to lymph nodes 75% with distant metastasis Specificity and positive predictive value increases with higher cutoff levels
CEA as a Screening Test - Conclusion Clinically, CEA has no role as a screening test for any malignancy While it has been demonstrated that CEA elevations are associated with increased allcause mortality, it s use as a test for risk selection remains highly controversial
ASSIST WITH DIAGNOSIS
Tumor Markers That Assist with Diagnosis Tumor Marker Cancer Type Tissue Analyzed Alpha-fetoprotein (AFP) Liver cancer Blood BCR-ABL fusion gene CML Blood &/or bone marrow CA-125 Ovarian Blood Calcitonin Medullary thyroid cancer Blood Chromogranin A (CgA) Neuroendocrine tumors Immunoglobulins Multiple myeloma & Waldenström macroglobulinemia Blood Blood or urine
Tumor Markers That Assist with Diagnosis Tumor Marker Cancer Type Tissue Analyzed KIT Prostate-specific antigen (PSA) GI stromal tumor & mucosal melanoma Prostate cancer Tumor Blood
Case Study Assisting with Diagnosis 63 y.o. male applying for $750,000 20-year Term Paramedical exam is unremarkable Labs reveal calcium level at upper limits of normal, serum globulin level slightly greater than serum albumin level, and small amount of protein in the urine APS reveals recent physical with mild anemia Referred back to his AP for further evaluation Follow-up labs revealed a monoclonal IgG kappa spike, with Bence-Jones protein in the urine Bone marrow aspirate and biopsy showed increased number of plasma cells
DETERMINE PROGNOSIS
Tumor Markers That Help Assess Prognosis Tumor Marker Cancer Type Tissue Analyzed ALK gene rearrangements Non-small cell lung cancer & anaplastic large cell lymphoma Alpha-fetoprotein (AFP) Germ cell tumors Beta-2-microglobulin (B2M) Beta-human chorionic gonadotropin (ß-hCG) EGFR mutation analysis Lactate dehydrogenase (LDH) Multiple myeloma, CLL, & some lymphomas Choriocarcinoma & testicular cancer Non-small cell lung cancer Germ cell tumors Tumor Blood Blood, urine or CSF Blood or urine Tumor Blood
Tumor Markers That Help Assess Prognosis Tumor Marker Cancer Type Tissue Analyzed Urokinase plasminogen activator (upa) & plasminogen activator (PAI-1) 5-Protein signature (Ova1) 21-Gene signature (Oncotype DX) 70-Gene signature (Mammaprint) Breast cancer Ovarian cancer Breast cancer Breast cancer Tumor Blood Tumor Tumor
GUIDE THERAPY
Tumor Markers That Help Guide Therapy Tumor Marker Cancer Type Tissue Analyzed ALK gene rearrangements BRAF mutation V600E Non-small cell lung cancer & anaplastic large cell lymphoma Cutaneous melanoma & colorectal cancer Tumor Tumor CD20 Non-Hodgkin s lymphoma Blood EGFR mutation analysis Estrogen receptor (ER)/ Progesterone receptor (PR) Non-small cell lung cancer Breast cancer Tumor Tumor
Tumor Markers That Help Guide Therapy Tumor Marker Cancer Type Tissue Analyzed HER2/neu KIT KRAS mutation analysis Breast cancer, gastric cancer & esophageal cancer Gastrointestinal stromal tumor & mucosal melanoma Colorectal cancer & non-small cell lung cancer Tumor Tumor Tumor
Case Study Guide to Therapy 42 y.o. female applying for $1,000,000 UL In March, 2010, she was found to have a 1.5 cm left breast mass Needle biopsy revealed poorly differentiated infiltrating ductal adenocarcinoma She underwent lumpectomy followed by radiation therapy Pathology on the lumpectomy specimen revealed a 1.5 cm poorly differentiated adenocarcinoma with clear margins; sentinel lymph node biopsy was negative ER/PR receptors were negative; HER2/neu was positive
EVALUATE RESPONSE TO TREATMENT
Tumor Markers That Determine Response to Therapy Tumor Marker Cancer Type Tissue Analyzed Alpha-fetoprotein (AFP) Liver cancer & germ cell tumors Beta-2-microglobulin (B2M) Beta-human chorionic gonadotropin (ß-hCG) Multiple myeloma, CLL, & some lymphomas Choriocarcinoma & testicular cancer Blood CA15-3/CA27.29 Breast cancer Blood CA19-9 Pancreatic cancer, gallbladder cancer, bile duct cancer, & gastric cancer Blood, urine or CSF Urine or blood Blood
Tumor Markers That Determine Response to Therapy Tumor Marker Cancer Type Tissue Analyzed CA-125 Ovarian cancer Blood Calcitonin Medullary thyroid cancer Blood Chromogranin A (CgA) Neuroendocrine tumors Blood Fibrin/fibrinogen Bladder cancer Urine HE4 Ovarian cancer Blood Nuclear matrix protein 22 Prostate-specific antigen (PSA) Bladder cancer Prostate cancer Urine Blood Thyroglobulin Thyroid cancer Blood
Case Study Response to Therapy 28 y.o. male applying for $500,000 30-year Term In 2009, found to have a testicular mass Orchiectomy was performed, with pathology revealing mixed embryonal cell and teratocarcinoma Metastatic evaluation showed retroperitoneal lymph node enlargement, and a 4 cm hilar mass ß-hCG was elevated at 75 miu/ml (0-5 miu/ml) and AFP was elevated at 27 µg/l (<10 µg/l) He received 4 cycles of chemotherapy, with return of tumor markers to normal, and resolution of the retroperitoneal adenopathy A 2 cm residual hilar mass remains, and is stable
DETECTION OF RECURRENCE
Tumor Markers Used to Detect Recurrence Tumor Marker Cancer Type Tissue Analyzed Alpha-fetoprotein (AFP) Beta-human chorionic gonadotropin (ß-hCG) Liver cancer & germ cell tumors Choriocarcinoma & testicular cancer Blood CA15-3/CA27.29 Breast cancer Blood CA-125 Ovarian cancer Blood Calcitonin Medullary thyroid cancer Blood Carcinoembryonic antigen (CEA) Colorectal cancer & breast cancer Blood or urine Blood
Tumor Markers Used to Detect Recurrence Tumor Marker Cancer Type Tissue Analyzed Chromogranin A (CgA) Chromosomes 3, 7, 17 & 9p21 Cytokeratin fragments 21-1 Neuroendocrine tumors Bladder cancer Lung cancer Blood Urine Blood HE4 Ovarian cancer Blood Immunoglobulins Prostate-specific antigen (PSA) Multiple myeloma & Waldenström macroglobulinemia Prostate cancer Blood or urine Blood Thyroglobulin Thyroid cancer Blood
Case Study Tumor Recurrence Monitoring 67 y.o. male applying for $10,000,000 UL In 05/2004, presented with PSA = 5.7 ng/ml DRE was negative, TRUS showed no masses, TRUSguided biopsies revealed Gleason s 6 prostate cancer in 5/12 cores Treated with radical prostatectomy Path showed Gleason 7 prostate cancer in both lobes, margins and seminal vesicles clear Post-op PSA <0.04 ng/ml PSA in 4/13 was 0.1 ng/ml Current PSA is 1.2 ng/ml