Keeping Current  |  Nurse-to-Nurse Forum  |  Resources  |  Side Effect and Symptom Management  |  Breaking News  |  Events

[ Overview of CRC (1/3) ] [ Overview of CRC (2/3) ] [ Overview of CRC (3/3) ] [ Metastasis ] [ Ablation ] [ Colonic Polyps ]
[ Elderly Treatment ] [ Genomics in CRC (1/2) ] [ Genomics in CRC (2/2) ] [ Herbal Supplements ] [ Survivorship ] [ Drug Interactions ]
[ Case Study 1 ] [ Case Study 2 ]

Genomics in CRC 1/2

Rule

The Role Of Molecular Markers 

The field of genomics has expanded exponentially for the disease of cancer. Ongoing research in this area is helping clinicians better define the CRC disease process and improve treatment for this common but preventable cancer. Although there are many areas under study in this field, one particular area that may directly affect oncology nurses and their practice is in molecular markers for CRC. Molecular markers have long played a significant role in the treatment of breast cancer with the routine testing of estrogen and progesterone receptors, and there are specific markers that can help to predict response to therapy in CRC and other tumor types, providing clinician guidance for deciding which stage cancer patients would derive benefit from potentially toxic chemotherapy. This is particularly important in stage II CRC, in which the disease has not yet invaded the lymph nodes. There are several subclassifications of stage II disease that may predict for more aggressive cancers needing additional therapy. Some of those factors include

  • Larger tumors
  • More aggressive histology
  • Lymph-vascular invasion
  • Inadequate lymph node sampling in the original cancer surgery

Rule

Predictive Markers

Although their use is not the standard of care in most clinical practice settings, predictive markers can help clinicians to identify which patients would benefit from adjuvant chemotherapy. Some of the markers under study include the following:

  • Microsatellite instability (MSI) tumors are common across different types of cancer and are present in two-thirds of sporadic colon cancers. The MSI is caused by mismatched repair genes, and there seems to be a link between the MSI and transforming growth factor mutation as well. Researchers have shown that CRC patients with MSI tumors have better recurrence-free intervals than their counterparts and, interestingly, do not derive benefit with the use of adjuvant chemotherapy.1 These high-frequency MSI (MSI-H) tumors may be resistant to fluorouracil (5-FU), with changes in the DNA mismatch repair system that decrease ability for cell death common to 5-FU.2 This genomic change may affect the prognosis of stage II and III CRC patients since MSI-H patients may not seem to respond to 5-FU therapy.3
  • K-ras is a gene essential to the growth and differentiation of extracellular signaling. In CRC, approximately 30% of patients have a mutation in the K-ras gene linked to increased risk of nodal metastasis and possibly more aggressive tumor behavior for this subset of patients.,1
  • TP53 is a tumor suppressor gene that is mutated in 40% to 60% of CRC patients and may have a role in both the patient’s prognosis as well as be a predictor of response to chemotherapy used in CRC.1 Patients with the TP53 mutation were found to have a poorer prognosis for both stage II and III disease when treated with surgery alone; however, studies report conflicting data regarding the role of TP53 in predicting response to adjuvant 5-FU therapy (1 study showed that patients with the TP53 mutation did not benefit clinically).

Rule

Predicting Response to Chemotherapy

Studies have examined the role of genomic markers in predicting response to chemotherapy, including unexpected toxicities. Although testing for these markers is not routine, if patients have signs of toxicity that are unexpected for their treatment protocols, testing for some of these markers should be considered.

  • 5-FU is the oldest drug for the treatment of CRC, approved for both adjuvant and metastatic disease, and kills cancer cells by inhibiting the nucleotide synthetic enzyme thymidylate synthase (TS) by its active metabolite fluorodeoxyuridine monophosphate (FdUMP), resulting in the depletion of thymidylate. Some studies have shown that TS can be both a predictive and prognostic marker in patients treated with 5-FU, and that overexpression of TS may lead to resistance to the drug.4 Low levels of thymidylate phosphorylase (TP) expression is also associated with response and survival in this disease; expression of TP may indicate more aggressive tumors that are less responsive to treatment.1,4 Patients with dihydropyrimidine dehydrogenase (DPD) deficiency may experience extreme toxicity with 5-FU therapy; DPD is essential in the metabolism of this drug.4 This deficiency can be fatal for patients, as it leads to a much higher systemic level of drug.1 Studies have shown that patients who had low expression of DPD experienced longer survival and disease-free recurrence, although some researchers have found the opposite to be true in patients treated with surgery alone.1 Further research in this area will continue to define the role of particular molecular markers in this disease.
  • Oxaliplatin is the standard of care for patients with node-positive CRC and is given in both the adjuvant and metastatic setting. Researchers have examined the role of ERCC1 (a protein involved in the NER pathway) and discovered that ERCC1 gene expression correlates with overall survival in patients receiving 5-FU and oxaliplatin chemotherapy for CRC in the refractor setting.1 ERCC1 mRNA and TS mRNA expression levels were also found to be independent predictive markers of survival for both 5-FU and oxaliplatin in 1 study of patients with progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy.5
  • Irinotecan is approved in the metastatic setting and functions as a DNA topoisomerase I inhibitor. The relationship between the DNA topoisomerase I activity and the sensitivity of cells to irinotecan is under study.1 Pharmacogenetic research has identified specific patient populations at risk for increased toxicity with irinotecan by their ability to metabolize SN-38, the active metabolite of the drug. Patients homozygous for the UGT1A1* 28 allele are at increased risk for neutropenia following administration of the drug and should be considered for a dose reduction.6
  • Capecitabine is an oral agent that functions as a 5-FU prodrug and mimics infusion of 5-FU; it is approved in both the adjuvant and metastatic setting. TP expression was found to be associated with response to capecitabine plus irinotecan for patients with metastatic CRC in 1 recently reported study, with time to tumor progression superior in patients with tumors that expressed TP and longer overall survival for positive expression as well.7
  • Cetuximab and panitumumab are monoclonal antibodies that target epidermal growth factor (EGF) by inhibiting the EGF receptor (EGFR). EGF may be expressed in 60% to 75% of CRC patients and overexpressed in approximately 50%; it is therefore an excellent target for therapy, and both agents are approved in the metastatic setting.1
  • Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), the ligand for the VEGF receptor. Because increased VEGF expression seems to correlate with a poorer prognosis and a higher recurrence rate,1 targeting CRC with an inhibitor of VEGF is an important clinical strategy. Bevacizumab is approved in the metastatic setting.

Rule

Molecular Markers

Molecular markers can help to determine the specific patient populations that will benefit from CRC therapy. Treatment therefore becomes individualized, with the goal of sparing patients who might not respond to potentially toxic chemotherapy.8 Studies have been conflicting in this area, and the recently published trial assessing TS and DPD expression in patients receiving 5-FU/LV did not show higher response rates; more research is therefore needed.9 Two very recent papers have also indicated that the correlation between MSI-H tumors and chemotherapy response is still not completely understood, and research in this area has shown inconsistent results as well.10 It may be that the benefit is more pronounced for its ability to serve as a marker for prognosis and response in Lynch syndrome families (an hereditary nonpolyposis CRC syndrome) versus sporadic colon cancers.11

A commercial test now exists (Invader UGT1A1 Molecular Assay; Third Wave Technologies, Inc) to test patients for the UGT1A1* 28 allele, and some clinicians believe that all new patients should be tested prior to beginning therapy with irinotecan.6 This is an exciting time to be participating in the care of patients with CRC, but it is incumbent on all oncology nurses to stay abreast of new developments in the treatment of this patient population. Although the use of molecular markers is just beginning, these specialized examinations may benefit some patients.

Rule

References

  1. Allen WL, Johnston PG. Role of genomic markers in colorectal cancer treatment. J Clin Oncol. 2005;23:4545-4552.
  2. Jo, WS, Carethers, JM. Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomark. 2006;2:51-60.
  3. Benatti P, Gafa R., Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332-8340.
  4. Igbal S, Lenz HJ. Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Reports. 2001;3:102-108.
  5. Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 2001;19:4298-4304.
  6. O’Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT)1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol. 2006;24:4534-4538.
  7. Meropol NJ, Gold PJ, Diasio RB, et al. Thymidine phosphorylase expression associated with response to capecitabine plus irinotecan with metastatic colorectal cancer. J Clin Oncol. 2006;24:4069-4077.
  8. Allen WL, Coyle VM, Johnston PG. Predicting the outcome of chemotherapy for colorectal cancer. Curr Opin Pharmacol. 2006;6:332-336.
  9. Smorenburg CH, Peters GJ, van Groeningen CJ, et al. Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluorouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase. Ann Oncol. 2006;17:35-42.
  10. Kim GP, Colangelo, LH, Wieand S, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. 2007;25:767-772.
  11. Boland CR. Clinical uses of microsatellite instability testing in colorectal cancer: an ongoing challenge. J Clin Oncol. 2007;25:754-756.

Rule

Key Definitions

dihydropyrimidine dehydrogenase (DPD)—the principal enzyme involved in the degradation of fluorouracil (5-FU); thymidylate phosphorylase—the first enzyme in the metabolic activation pathway of 5-FU; nucleotide synthetic enzyme thymidylate synthase (TS)—the target enzyme of the antimetabolite 5-FU. These 3 proteins assessed together have been indicated as possible predictive markers of 5-FU–based treatment

ERCC1 mRNA—a key enzyme of the repair pathway associated with response and survival in 5-FU–refractory patients with metastatic colorectal tumors undergoing 5-FU/oxaliplatin combination chemotherapy

fluorodeoxyuridine monophosphate (FdUMP)—the end metabolic process of 5-FU

genomics—the study of an organism’s genome that includes the DNA sequence, structure, and regulatory mechanisms. The goal is to find each gene to develop medicines and predict susceptibility of diseases. Proteomics is the study of the proteins expressed by the genetic material

mismatched repair genes—genes that fix problems arising during DNA replication when bases are incorrectly paired. Patients with a variant of a DNA repair gene, known as MLH1, may have an increased risk of a subtype of CRC

molecular marker (biomarker, genetic marker)—fragment of a DNA sequence that indicates the presence of a disease state. DNA sequences in most patients with CRC are either short or long and fluctuate. These sequences are called microsatellites. Their fluctuation is termed microsatellite instability (MSI)

tumor suppressor gene—any of a class of genes (as TP53) that act in normal cells to inhibit unrestrained cell division and through mutation place the cell at increased risk for malignant proliferation; also called antioncogene

UGT1A1*28 allele—a genetic marker that can be screened for determining the proper dosage of irinotecan for persons with CRC or other types of cancer as well as susceptibility to neutropenia

Rule

Read More

Rule

[ Previous Page ] [ Home ]

This page was last modified on 5/14/2007, at 12:16:05 pm ET.