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Originally published as JCO Early Release 10.1200/JCO.2003.04.156 on July 28 2003 © 2003 American Society for Clinical Oncology
Will Identifying or Targeting Altered Marker Expression in Response to Cytotoxic Therapy Be of Prognostic or Therapeutic Value?
1 Department of Radiation Oncology THE FUTURE of oncology will undoubtedly involve the detection, validation, and targeting of tumor-specific molecules. Identifying the targets, developing target-specific interventions, and validating biologic effects of an intervention are daunting tasks. Molecular target expression is almost certainly a dynamic phenomenon. As populations of heterogeneous tumor cells are exposed to the stress of cytotoxic therapy, identifying the targets is made even more complex. Proportions of cells expressing a particular marker profile can change in response to this stress and through selection of the most resistant cells in a population. In this issue of the Journal of Clinical Oncology, the first published manuscript evaluating tumor marker expression before and after preoperative cytotoxic therapy is presented.1 Pretreatment tumor samples were compared with samples from the surgical specimen in patients treated with chemoradiation with and without regional hyperthermia as preoperative therapy for rectal cancer. Pretreatment biomarker levels did not correlate with outcome, and a decrease in immunohistochemical expression of p21Waf1/Cip1 cyclin-dependent kinase inhibitor and an increase in Ki-67 proliferation marker in response to chemoradiation seemed to predict improved disease-free survival. The authors postulate that the induction of p21Waf1/Cip1, therefore, is a novel mechanism for resistance to chemoradiation.1 Their findings are of interest because they address the question of altered ("dynamic") marker expression in response to cytotoxic therapy. In addition, the results can be understood and explained in a rational way with supportive evidence from preclinical and model system studies. But, the question remains: are the findings valid or simply a surrogate for something that we already knew? As the authors acknowledge, the significant limitation of this study is the inability to control for known prognostic variables that have been demonstrated in many prospective and retrospective studies, including T and N stage, sex, and tumor grade. Without a multivariate analysis, is it possible that the improved outcome seen with decreased p21Waf1/Cip1 and increased Ki-67 could have been due to the a priori risk of tumor recurrence, as predicted by known prognostic factors, rather than a unique cellular response with an independently significant cause and effect. Only a univariate analysis was performed, presumably as a result of small numbers of patients. Response to therapy was predictive of better outcome, but this result adds value only if it is independent of other known prognostic factors. Smaller, more favorable tumors could have responded better (relative to other patients in the study) to the cytotoxic/hyperthermic intervention and accounted for the improved outcome. Similarly, the correlation of decreased p21Waf1/Cip1 and increased Ki-67 expression on univariate analysis with disease-free survival could simply be a substitute for other known or unexplored prognostic factors. There have been many hundreds of papers relating outcome to p53 gene status in tumors of patients with a variety of tumor types, and p21Waf1/Cip1 is well-known to be regulated by wild-type p53 and to participate in control of cell proliferation. The majority of reported studies have assessed pretreatment expression and are flawed because of different treatments and different prognostic groups unaccounted for in the analyses. In an analysis of published studies in colorectal cancer, the authors concluded that p53 expression is not likely to be of value as an independent prognostic factor.2 A meta-analysis was conducted, which assessed the same question among patients with breast, ovarian, and head and neck cancers. Forty-five of the 301 identified studies received relatively homogeneous treatment and were felt to have adequately corrected for important prognostic factors. Although publication bias could have affected the result, a nearly significant negative effect of p53 overexpression (which is often due to p53 gene mutation) on outcome of treatment with cytotoxic drugs or radiation was found among this group of studies.3 In the current study, patients have not received homogeneous treatment, and known prognostic factors have not been taken into account. As such, the results of this study are not generalizable, but are valuable as background for further study. Therefore, this study is interesting not so much because it definitively answers questions, but because it generates testable hypotheses and focuses attention on markers that respond to intervention, rather than the baseline status of potential markers. Future validation of the prognostic significance of these findings must be validated in the context of known prognostic factors, which could then lead to more rational therapeutic intervention. Obviously, the hypothesis that is most interesting is whether the induction of genes acting in DNA damage response pathways represents an independent mechanism of cellular resistance to cytotoxic therapy that can be targeted. Such strategies (eg, the disruption of cell cycle checkpoint control by flavopiridol in patients treated with cytotoxic therapy4) are in early clinical development. REFERENCES
1. Rau B, Sturm I, Lage H, et al: Dynamic expression profile of p21Waf/Cip1 and Ki-67 predicts survival in rectal carcinoma treated by preoperative radiochemotherapy. J Clin Oncol 21:3391–3401, 2003 2. Petersen S, Thames HD, Nieder C, et al: The results of colorectal cancer treatment by p53 status: treatment-specific overview. Dis Colon Rectum. 44:322–334, 2001[CrossRef][Medline] 3. Thames HD, Petersen C, Petersen S, et al: Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A treatment-specific overview of the clinical data. Strahlenther Onkol 178:411–421, 2002[Medline]
4. Schwartz GK, O’Reilly E, Ilson D, et al: Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20:2157–2170, 2002
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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