Effect of Pre-Clinical Research on Cancer Disparities to Evidence-Based Care
Upender Manne Associate Professor, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA, 35226
Abstract:
Colorectal cancer (CRC), the third most common cancer, is found predominately in countries that practice the Western diet. The pathologic stage, most commonly used for prognosis, may not be the best indicator of outcome, since patients with tumors of identical stage have different treatment responses and outcomes. Thus, there is a need to identify predictors of therapy efficacy, disease recurrence, and patient survival.
Due to contradictory results, no marker has achieved acceptable clinical utility. These differences may be due to technical discrepancies, under-powered study populations, an admixture of different proportions of racial/ethnic/geographic groups, or to different tumor sites within the colorectum, tumor stages, and/or patient demographics. Abnormal nuclear accumulation of p53 in CRC cells is a strong indicator of poor patient survival of non-Hispanic Caucasians (CAs) with proximal colon tumors. C:G to T:A transitions at CpG sites are predominant in CAs but less common in African-American (AAs). In AAs, but not CAs, the Pro/Pro phenotype correlates with a higher incidence of missense p53 mutations, nodal metastasis, and higher mortality due to CRC. p53, however, has no prognostic value for AAs or CAs with distal or rectal tumors. Establishment of race-based differences in p53 may aid in identifying patients with aggressive phenotypes.
Lack of or decreased expression of Bcl-2 as a strong predictor of early disease recurrence and of a poor prognosis, particularly among patients with Stage II tumors; in contrast, increased expression of p27kip-1 is an indicator of good prognosis for patients with Stage III tumors. Patients with CRCs expressing high levels of Bax have worse survival when they receive chemotherapy; however, patients treated only with surgery and with CRCs lacking Bax expression had 5.33 times higher mortality than those with high Bax expression. Further, analysis of a panel of six miRNAs suggests that, after treatment, patients with higher levels of miRNA-21 and miR-106a have an increased risk of death. For AA patients, but not for CAs, the presence of higher levels of miR-181b and miR-203 indicate a poorer prognosis.
Molecular markers associated with CRCs have biologic consequences based on tumor location, pathologic stage, and race/ethnicity of the patients. Thus, potential confounding variables, such as tumor stage, location, and patient race/ethnicity should be taken into consideration; the proximal colon, the distal colon, and the rectum should be considered as separate organs; and results across all data sources should be considered in evaluating racial differences in cancer outcomes. Identification of testable models would yield valuable information on patient outcomes.
To establish personalized medicine, research should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapies to target these molecules. Such strategieshave the potential of reducing the personal and socio-economic burden of cancer.
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Keywords: colorectal cancer, preclinical research, race/ethnicity, Bcl-2, p53, p27, miRNA, and personalized medicine
