Clinical Pharmacogenetics

The determination of the clinical utility of pharmacogenetics is currently a high research priority in oncology. A large number of important genetic determinants have been identified thus far in tumors, but the clinical relevance of most of them currently remains unconfirmed because the data correlating specific tumor markers with survival or therapeutic response have been limited by the (i) small number of patients screened due to the difficulties in obtaining suitable tissue samples, (ii) lack of studies primarily designed to detect specific correlations between gene abnormalities and drug response or disease prognosis, and (iii) marked variability in analytical methodology and lack of quality controls among different studies. TP53 and ErbB2 represent a sound example of the problematic link between the choice of reference methodology and the determination of clinical utility. These genes may be analyzed by different methods, including sequencing, fluorescence in situ hybridization, and immunohistochemistry, but even for a single type of analysis, the specific methodological procedure and the interpretation criteria may be subjected to considerable variability.

TP53 is the most widely studied gene in gastrointestinal cancer; however, it has not been validated as a prognostic marker, despite the large number of articles published in the scientific literature and the continuous interest in methodologic improvement with the aim of making genetic analysis feasible for routine use. Indeed, there is no single guideline in gastrointestinal oncology that currently recommends the routine analysis of TP53 status for the assessment of prognosis or drug response. This is despite the evidence that a high proportion of mutations are present in colorectal tumors (upto 73.4% cases). Furthermore, using multivariate Cox proportional-hazards analysis, TP53 gene mutations were found to be a significant and independent predictor of poor prognosis in colorectal cancer (102). To facilitate the transition of molecular markers from the laboratory to the clinic, rigorous standardization of analytical methods and tissue banking (i.e., neoplastic tissue sampling, lymphocytes, tumor protein, and DNA recovered from peripheral blood) (Fig. 15), and the incorporation of these into large clinical studies, is required. Therefore, accurate genetic profiling of tumors and optimally designed human trials are the most important points for future application of pharmacogenetics to the management of patients with cancer. With respect to the genetic profiling of tumors, it will be crucial to identify (i) the genetic abnormalities involved in tumorigenesis and disease prognosis, (ii) the genes affecting drug response, and (iii) the degree of overlap between the two groups. With respect to clinical trial design, the relevant genetic markers associated with disease progression and prognosis could be characterized in

Figure 15 Sources of nucleic acids and proteins for genomic and proteomic profiling of tumors and patients. Abbreviations: RTQ-PCR, real-time, quantitative polymerase chain reaction; FISH, fluorescence, in situ hybridization; IHC, immunohistochemistry; PBMNC, peripheral blood mononucleated cells. Source: From Ref. 92.

Blo vesi

Blo vesi

PBMNC

M ^ Tissue sampling -

COOH PBMNC -

dNA/RNA analysis (^array, sequencing, RTQ-PCR, FISH) Protein analysis (|jarray, enzyme assay, IHC, immunoblotting)

PBMNC

case-control studies, while retrospective analysis may be used to identify genetic alterations associated with drug efficacy (predictivity) (Fig. 16). For example, a recent population-based case-control study demonstrated the presence of a common A870G polymorphism in the cyclin D1 (CCND1) gene, the CCND1 870A genetic variant being associated with clinically aggressive colorectal cancer (103). The complexity of the problem is evidenced by the observation in another case-control study of CCND1 A870G genotype, which showed no correlation between the presence of the A allele and tumor pathology or patient survival (104). Retrospective studies revealed important correlations between MSI, survival, and the benefit of adjuvant 5-FU chemotherapy in stages II and III colon cancer. Patients not given adjuvant chemotherapy, whose tumors displayed high-frequency MSI (H-MSI), had a better 5-year survival than patients with low-frequency MSI (L-MSI) or MSS. In contrast, adjuvant chemotherapy with 5-FU improved overall survival among patients with MSS or L-MSI tumors, but no benefit was obtained with adjuvant chemotherapy in the group with H-MSI (105).

Therefore, a critical reappraisal of the role and clinical burden of the many genetic abnormalities detected in solid tumors is needed. Despite the tremendous advances in the comprehension of the molecular and genetic pathways leading to solid tumors, such progress has not yet been translated into better management of patients with cancer (106). Hopefully, translation of novel knowledge into clinical practice may be overcome by the results of well-designed prospective clinical trials in which direct comparison is performed between patient treatment selected on the basis of conventional criteria versus treatment selection based on tumor genotype (Fig. 16).

Figure 16 Identification of genetic abnormalities associated with disease progression in case-control studies and those associated with drug response in retrospective studies. The validation of the predictive power of genetic profiling within the clinical setting requires the design of ad hoc randomized clinical trials in which patients are stratified according to their disease genotype and managed specifically or treated empirically with conventional stratification based on clinicopathologic factors known to influence disease outcome. Abbreviation: TS, thymidylate synthase.

Figure 16 Identification of genetic abnormalities associated with disease progression in case-control studies and those associated with drug response in retrospective studies. The validation of the predictive power of genetic profiling within the clinical setting requires the design of ad hoc randomized clinical trials in which patients are stratified according to their disease genotype and managed specifically or treated empirically with conventional stratification based on clinicopathologic factors known to influence disease outcome. Abbreviation: TS, thymidylate synthase.

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