Prognostic Cancer Biomarkers
The genetic diversity associated with cancer cells are shocking huge; and identifying a suitable prognostic marker is a real challenge. Prognostic cancer markers aims to evaluate objectively a patient’s overall outcome, response to treatment and chances of cancer recurrence. Prognostic markers can also help to select patients for a particular treatments and help predict the beneficial effect of the therapy. DNA, RNA, epigenetic patterns, signaling pathways, proteins, and metabolic biomolecules have been used as prognostic cancer markers. (Mehta et al., 2010)
Given below are few prognostic biomarkers commonly used in cancer medicine:
1. Beta tubulin: Beta tubulin regulates microtubule assembly in the cell. Class III tubulin are expressed by tumor of both neuronal and non-neuronal origin. High expression of beta tubulin confers worst prognostic outcome. Overexpression of class III beta tubulin was associated with paclitaxel resistance and poor prognostic outcome in ovarian cancer (Fernandina, 2006).In another retrospective study, overexpression of class III beta tubulin was associated with unfavorable prognosis in patients with curatively resected non-small cell lung cancer(NSCLC) (Koh et al., 2010). This biomarkers is of prognostic significance in many other solid cancers as well. The level of expression of this marker is estimated using immunohistochemistry staining of biopsy samples. Patients expressing high level of this marker had poor prognosis (Koh et al., 2009).
2. BRCA1: Increased expression of BRCA1 is reported with poor prognosis of breast cancer and NSCLC. Germ line mutation of this gene is reported in majority (40% -80%) of breast cancer cases. It is also used to predict cancer occurrence. The risk of occurrence of breast and ovarian cancer is high in women with this mutation. BRCA1/2 mutation related tumors are associated with increased risk for malignancies and are sensitive to platinum based therapy. (Mehta et al., 2010)
3. CA19-9: is an O- linked glycolipid expressed on the cell surface and has been identified in the tissue and sera of patients with gastrointestinal, biliary and pancreatic tumors. Though this markers have poor sensitivity in early detection of tumor, it gives a reliable prognosis about the aggressiveness of cancer in diagnosed and treated individual. It is used as a specific marker for pancreatic cancer. Due to its poor sensitivity, it cannot be used as a screening tool. Elevated serum levels above 100U/ml suggest advanced and metastatic pancreatic cancer. Decrease in CA19-9 after pancreatic resection is associated with prolonged survival. On the other hand, elevated CA19-9 or failure of decrease after pancreatic resection is indicative of metastasis and poor prognosis.
4. CAIX: Carbonic anhydrase IX (CAIX is a potential marker for evaluating the metastatic nature of clear cell renal cell carcinoma. However few researchers have found it futile as a prognostic markers on patients receiving Sorafenib treatment (Choueiri et al., 2013). Paraffin embedded tissue tumors are used to detect CAIX expression.
5. CD44: Patients who are positive for this marker have favorable prognosis, while those who are negative have poor prognosis. CD44 is used in combination with other markers like CD24 to detect cancer stem cells. CD44 has been particularly useful in predicting the prognosis of bladder carcinoma. Its effectiveness in other carcinoma is still disputed. Tissue microarray or FAC is used to study the expression of this marker. The disadvantage with this marker is that it has different splice variant, and the expression of splice variants rather than the CD44, is of prognostic significance. It was also found to provide unreliable prognosis in certain situations and not reliable when considered individually. This antigen can be measured in blood cells. (Mehta et al., 2010)
6. CEA: Carcinoembryonic antigen level increases in the cancers of colon and rectum. CEA levels are measured both before and after resection. High CEA levels before surgery is associated with poor prognosis. This antigen is measured in blood and is a reliable prognostic marker for colo-rectal cancer. This cannot be used as a screening or diagnostic marker as it is elevated in the blood of smokers and patients with inflammatory condition. The level in normal individual varies from 2.5-5 ng/ml. CEA levels are also tested in other cancers like lung, breast, gastrointestinal and gynecologic cancer. Patient who have CEA levels >10ng/ml have worst outcome.
7. c-kit: is a tyrosine kinase receptor. A positive expression of c-kit is associated with decreased survival likelihood in small cell lung cancer. This marker is particular relevant in advanced stages of diseases and in those having poor response to chemotherapy. The mean survival was 71 days in c-kit positive patients when compared to 278 days in c-kit negative patients who don’t respond to chemotherapy (Micke et al., 2001). A mutation in the exon region of c-kit gene was associated with good prognosis of gastrointestinal stromal tumors. Those positive for c-kit expression had higher frequency of recurrence and higher mortality than those who are negative for c-kit.
8. ColoPrint: assay was released as a prognostic marker for colon cancer in 2013. The aim was to predict recurrence in patients and reduce the risk. This is a gene expression profiling kit. It allows screening for, expression levels of 38 different signature gene specific to colon cancer. This test was found to have prognostic significance in patients with colon cancer. The predictive and prognostic value of this test needs to be validated in a larger sample. (Sharif and O’Connell, 2012)
9. CTC (circulating tumor cells) in peripheral blood are used as markers of cutaneous melanoma. It is used in clinical trials and daily clinical evaluation. The results are highly specific and sensitive in determining the success of treatment and outcome for patients. CTC appears in the blood during early stages of cancer progression and were detected in 29% of primary melanoma. The level of CTC increases as the tumor increases in size and metastasis. (Xu and Zhong, 2010). CTC was also found to have prognostic significance in colo-rectal cancer, breast cancer and prostate cancer.
10. Cyclin D1 is an important regulator of cell cycle progression and a regulator of transcription. Cyclin D1 overexpression has been reported in different cancer types. The frequency of occurrence is high in head and neck squamous cell carcinoma. It helps to predict tumor growth, recurrence and metastasis. It was also suggested as therapeutic target. (Musgrove et al., 2011). It is used often in the clinics to suggest prognoses of bladder cancer.
11. Cyclin E is yet another master regulator of cell cycle. Its deregulation can lead to tumorigenesis. They are expressed in high levels in fastly dividing tumor cells. The hazard ratio for death in breast cancer patients expressing cyclin E was 13.3 fold higher than people with low cyclin E. It is also used as a prognostic marker in bladder cancer.
12. E-Cadherin: is a calcium dependent epithelial cell adhesion molecule. Loss of E –cadherin is associated with many human cancer cell. Loss of E-cadherin is positively correlated with metastasis. It is used as a prognostic marker for bladder and breast cancer. (Mehta et al., 2010)
13. EGFR: belongs to receptor tyrosine kinase family. Overexpression and interaction between different signaling networks is associated with transformation. EGFR acts as a strong prognostic marker in breast, ovarian, head, neck, bladder and esophageal cancer. Increased expression in this marker, is associated with recurrence and overall survival. It provides modest prognostic information. Patients with high EGFR expression respond favorable to anti-EGFR therapies. (Normanno et al., 2006)
14. Estrogen: Patient’s estrogen positive breast tumor cell have better survival than estrogen negative breast tumor cells. (Mehta et al., 2010)
15. HER-2/neu gene overexpression is a sign of poor prognosis for breast and bladder cancer. Anti-HER2 antibody treatment in patients overexpressing HER-2/neu gene, can delay recurrence and reduce metastasis rate. HER-2/neu is a transmembrane tyrosine kinase receptor. (Mehta et al., 2010)
16. HER3 belongs to the epidermal growth factor receptor family. Overexpression of this gene is associated with increased proliferation, metastasis, and poor survival rate in melanoma patients.
17. ING3 and ING4: Reduced expression of these genes is associated with poor survival in Melanoma patients. These genes are necessary for apoptosis of cells, damaged by UV rays.
18. Ki-67 is a cell proliferation protein. Overexpression of this protein is associated with poor survival in breast cancer and bladder cancer. (Mehta et al., 2010)
19. K-ras is an oncogene and its mutation is considered as prognostic marker for NSCLC. Mutation is associated with poor survival rate.
20. Mamma print is a prognostic test used to evaluate the outcome of breast cancer in patients. It is a microarray based test that studies the expression of 70 genes.
21. Mammostrat on the other hand uses a panel five immunohistochemically markers: SLC7A5, HTF9C, P53, NDRG1, and CEACAM5, to predict the response to aromatase inhibitor treatment.
22. MMP-2 is a metalloprotease and its overexpression is associated with poor prognosis and survival in bladder cancer.
23. MSI: Non-polyposis colon cancer and Lynch syndrome patients with MSI syndrome, have DNA mismatch repair inactivation associated chromosomal instability. High frequency of MSI in stage II colon cancer is associated with better survival and lower relapse. (Mehta et al., 2010)
24. Oncotype –Dx is a microarray based prognostic test used to determine relapse in breast cancer patients. It studies the expression of 21 gene signatures.
25. p21, p53 and Rb are cell cycle regulator and overexpression of these genes and their proteins, is associated with poor prognosis of carcinoma. (Mehta et al., 2010)
26. PR: Expression of progesterone receptor is a favorable prognostic marker for breast and ovarian cancer cells.
27. RRMI: High expression of ribonuclease reductase inhibitors (RRMI) offers better prognosis in NSCLC.
28: VEGF: Overexpression of vascular endothelial growth factor is associated with poor prognosis in many solid tumors. (Mehta et al., 2010)
Challenges in identifying and using prognostic markers for cancer: Gene mutations are considered unreliable biomarkers to predict diseases prognosis, as these mutations evolve as the cancer progresses. Similar tumors can have a wide diversity of prognostic markers. For example, the markers which works for lung cancer in one population, may not be suitable for the other. Majority of the prognostic markers are identified by immunohistochemistry, FISH and microarray of tissue biopsies. The disadvantage of this being; it necessitates repeated biopsy procedures to confirm diagnosis. Biopsy is invasive than blood collection procedures. Very few biomarkers were found suitable in patient serum and these makers lacked specificity. MicroRNA based expression signatures are used as prognostic markers in Leukemia.
Tumor DNA mutation based biomarkers can also help to spot cancers resistant to drugs and thus reduce the use of expensive drugs in the wrong patient. However there are many caveats of considering circulating tumor DNA as prognostic markers, mainly because there is still a lot of lacunae in our understanding on which mutations to look for. A focused sequencing approach is necessary to help determine the type of mutations in cancer cell type. This however requires time and effort in these direction. Another disadvantage with these biomarkers is that they can fail to detect cancer in early stages.
Detecting a mutation does not necessary mean that there is a drug to cure the cancer. As long as there are no drugs to treat these mutations, these markers don’t have any prognostic significance. Further low risk SNP mutations in alleles are not suitable for screening large population for cancer risk. However these markers may provide an understanding on how cancer evolves. Nevertheless certain exceptional germline mutation of gene BRCA1, BRCA2, VHL, TP53 are associated with cancer risk. The cancer genome atlas research network 2011 has reported that more than 96% cancers have mutation in TP53 gene. KRAS mutations has been reported in many malignancies of the colon. Fusion transcript TMPRSS2-ERG are identified in certain fraction of prostate cancer. The problem with relying on genetic biomarkers is that they are expressed by a fraction of the cancer patients only, while rest have other rare mutation.
References
Choueiri, T., Cheng, S., Qu, A., Pastorek, J., Atkins, M. and Signoretti, S. (2013). Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: Analysis from the treatment approaches in renal cancer global evaluation trial (TARGET). Urologic Oncology: Seminars and Original Investigations, 31(8), pp.1788-1793.
Ferrandina, G. (2006). Class III Â -Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients. Clinical Cancer Research, 12(9), pp.2774-2779.
Koh, Y., Jang, B., Han, S., Kim, T., Oh, D., Lee, S., Kang, C., Kim, D., Im, S., Chung, D., Kim, Y., Kim, T., Kim, Y., Kim, J., Heo, D. and Bang, Y. (2010). Expression of Class III Beta-Tubulin Correlates with Unfavorable Survival Outcome in Patients with Resected Non-small Cell Lung Cancer. Journal of Thoracic Oncology, 5(3), pp.320-325.
Koh, Y., Kim, T., Jeon, Y., Kwon, T., Hah, J., Lee, S., Kim, D., Wu, H., Rhee, C., Sung, M., Kim, C., Kim, K. and Heo, D. (2009). Class III Â -tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma. Annals of Oncology, 20(8), pp.1414-1419.
Mehta, S., Shelling, A., Muthukaruppan, A., Lasham, A., Blenkiron, C., Laking, G. and Print, C. (2010). Predictive and prognostic molecular markers for cancer medicine. Therapeutic Advances in Medical Oncology, 2(2), pp.125-148.
Micke, P., Hengstler, J., Albrecht, H., Faldum, A., Bittinger, F., Becker, K., Wiewrodt, R., Fischer, B. and Buhl, R. (2004). c-kit Expression in Adenocarcinomas of the Lung. Tumor Biology, 25(5-6), pp.235-242.
Musgrove, E., Caldon, C., Barraclough, J., Stone, A. and Sutherland, R. (2011). Cyclin D as a therapeutic target in cancer. Nat Rev Cancer, 11(8), pp.558-572.
Normanno, N., De Luca, A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M., Carotenuto, A., De Feo, G., Caponigro, F. and Salomon, D. (2006). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366(1), pp.2-16.
Sharif, S. and O’Connell, M. (2012). Gene Signatures in Stage II Colon Cancer: A Clinical Review. Curr Colorectal Cancer Rep, 8(3), pp.225-231.
Xu, X. and Zhong, J. (2010). Circulating Tumor Cells and Melanoma Progression. J Investig Dermatol, 130(10), pp.2349-2351.
