Modification of Molecular Biology. for Colorectal Cancer Management

Transkript

1 Modification of Molecular Biology for Colorectal Cancer Management.. -

2 Genetic Progression Model of Colorectal Cancer

3 Molecular Events that Characterize the Transition to Adenocarcinoma years

4 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

5 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

6 Prediction of Susceptibility to Colorectal Cancer Half of sporadic CRC is associated with familial risk, yet the genetic basis for this common association is largely unknown Loss of imprinting (LOI) is an epigenetic phenomenon in which certain genes are generally silenced during embryonic development through the addition of methyl groups (methylation)

7 DNA-based Blood Test to Predict the Risk of Developing Colorectal Cancer LOI in the insulin-like growth factor II (IGF2) gene results in over-expression of IGF2 and increases risk of developing cancer

8 DNA-based Blood Test to Predict the Risk of Developing Colorectal Cancer LOI was present in 28% of persons with a family history of CRC and in 56% of those with a personal history of CRC In contrast, LOI was present in only about 10% of healthy individuals LOI in IGFII gene may be a valuable marker for identifying a subgroup of individuals at risk for developing sporadic colorectal cancer Cui, et al. Science 2003;299:

9 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

10 Survival for Colorectal Cancer by Stage

11 Cancer Biomarkers

12 Noninvasive Testing for Stool Tests Colorectal Cancer - Fecal occult blood tests - Colonocytes and protein products - Rectal mucus: Galactose Oxidase Schiff test - Multitarget DNA test Serum Tests - Serum markers (CEA, CA19-9, CA 242) - Proteomics - Nuclear matrix proteins - Serum DNA mutations

13 Molecular Stool Analysis Examine the stool for the presence of DNA with different mutations DNA is a good marker because - it is stable in the stool - it is shed continuously - through the amplification such as PCR, it can be detected in minute amounts

14 EXACT Sciences Corporation s s Test

15 Advantages of Stool DNA Mutation Testing Neoplasm specific Consistent markers Highly accurate User-friendly and non-invasive May allow for less frequent screening intervals Reduced false-positive results Ability to detect cancers proximal to colon

16 Limitations of Stool DNA Mutation Testing Lack of data from screening populations A need for test refinement Automation of the tests to reduce costs and improve efficiency Expense Patient acceptance/adherence

17 Fecal DNA vs Fecal Occult Blood for Colorectal-Cancer Cancer Screening Average-risk, asymptomatic persons 50 years of age or older Subjects (n = 4404) submitted one stool specimen for DNA analysis and Hemoccult II testing, and then underwent colonoscopy Fecal DNA panel detected 16 of 31 invasive cancers, whereas Hemoccult II identified 4 of 31 (51.6% vs. 12.9%, P=0.003) The DNA panel detected 29 of 71 invasive cancers plus adenomas with high-grade dysplasia, whereas Hemoccult II identified 10 of 71 (40.8% vs. 14.1%, P<0.001). The Colorectal Cancer Study Group NEJM 2004;351:

18 CEA in Colorectal Cancer The best available non-invasive technique for detection of recurrences in patients with a previous diagnosis of colorectal cancer Serial CEA testing detects recurrent disease with a sensitivity of 80% and a specificity of 70% Median lead-time of 5 months Most sensitive for detecting liver metastasis and least sensitive for detecting loco-regional disease

19 CEA in Colorectal Cancer Meta-analyses of outcome following intensive vs control follow-up Patients with intensive monitoring had a 9% better 5-year survival rate when CEA was included in the surveillance More than twice as many curative re-resections were performed for recurrent cancer Patients with intensive follow-up had a 3.6 times higher survival rate than the control group

20 CEA in Colorectal Cancer Patients with Dukes B (Stage II) and C (Stage III) who may be candidates for liver resection should be followed-up with 3 monthly CEA testing for at least 3 years after diagnosis American Society of Clinical Oncology (ASCO) Expert Panel European Group on Tumour Markers (EGTM)

21 Circulating Tumor Cell Enrichment Epithelial cells Leukocytes

22 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

23 Molecular Classification of Colorectal Cancer Current staging system is not sufficient. A need to identify predictive factors to guide identification of patients who are likely to experience relapse and possibly benefit from adjuvant therapy

24 Gene Expression Profiling by Microarray Analysis

25 Gene Expression Profiling by Microarray Analysis To identify genes that portend a poor prognosis To reveal genes associated with metastases To determine who will benefit from chemotherapy (responders vs nonresponders) To predict apoptotic response To avoid surgery in patients who would not benefit from resection

26 Gene Expression Profiles Predict Recurrence of Dukes B Colon Cancer Wang et al. J Clin Oncol 2004;22:

27 Gene-Expression Profiles Predict Recurrence of Dukes C Colorectal Cancer Arango et al. Gastroenterology 2005;129:874-84

28 Molecular Staging for Survival Prediction of Colorectal Cancer Patients Eschrich et al. J Clin Oncol 2005;23:

29 Molecular Staging for Survival Prediction of Colorectal Cancer Patients Eschrich et al. J Clin Oncol 2005;23:

30 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

31 Gene Profiles Predict Chemosensitivity and/or chemoresistance in Colon Cancer

32 Molecular Biology of Colorectal Cancer Prediction of susceptibility to cancer Early detection of cancer Molecular classification of cancer Prediction of treatment response Identify molecular targets and develop novel therapeutic strategies

33 Targeted Therapy A new generation of cancer drugs designed to interfere with a specific molecular target (typically a protein) that is believed to have a critical role in tumor growth or progression.

34 Epidermal Growth Factor Receptor EPIREGULIN HB-EGF AMPHIREGULIN EGF TGF-a BETACELLULIN HEREGULINS Aberrant expression of EGF receptors correlates with invasion and poor prognosis. O-charoenrat P, et al. Oral Oncology 2001 Cancer cells express several EGFR ligands that may enhance the growth of these tumor cell through potential autocrine, paracrine and juxtacrine pathways. TUMOUR CELLS EGFR/B1 O-charoenrat P, et al. Int J Cancer 2004

35 Strategies to Inhibit Growth Factor Signaling Immune effector cell Bispecific Abs Anti-VEGF mabs (eg bevacizumab) Ligand / toxin conjugate Anti-EGFR mabs (eg cetuximab) Nucleus Y EGFR tyrosine kinase inhibitors (eg gefitinib, erlotinib)

36 Survival Benefit of Systemic Rx in Metastatic Colorectal Cancer

37 Conclusion Molecular biology plays a crucial role in all aspects of colorectal cancer care. Early detection Diagnosis Prognosis Individualized selection of therapeutic combinations Novel therapy