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EDITORIALS |
From the Division of Clinical Pharmacology, Departments of Medicine and Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Correspondence: Address Correspondences to: Scott A. Waldman, M.D., Ph.D., F.C.P., 132 South 10th Street, 1170 Main, Philadelphia, PA 19107; Fax: 215-955-5681; E-mail: scott.waldman{at}jefferson.edu
Progression through the cell cycle is precisely coordinated to prevent replication of damaged DNA containing errors associated with genomic instability.1 Coordination is mediated, in part, by an integrated network of cyclin-dependent kinases that regulates transitions through different phases of the cycle. In turn, these kinases are regulated by inhibitors, including Cip/Kip family members p21/WAF/CIP1 and p27/kip1, which restrain progression of cells with damaged DNA by their arrest at specified checkpoints, preventing the perpetuation and accumulation of mutations that underlie neoplastic transformation.2
The central role of these kinase signaling pathways in maintaining the integrity of the genome is reflected in the observation that alterations in component proteins, for example through mutation, frequently contribute to molecular mechanisms underlying neoplastic transformation.1,2 Moreover, preservation of these signaling mechanisms in untreated tumors is often associated with a favorable prognosis, presumably reflecting the ability of these kinase cascades to limit genomic instability associated with neoplastic transformation.1,2 Indeed, specific proteins comprising these signaling pathways, including p27, may have utility as positive prognostic markers in the management of patients with cancer.2
Paradoxically, there is increasing recognition that the cell cycle plays a critical role in regulating the sensitivity of tumor cells to antineoplastic therapy.3 Indeed, expression of proteins imposing checkpoint control, including p21 and p27, may confer resistance to chemo- and/or radiotherapy, associated with a poor prognosis and an increased risk of developing advanced disease in patients.4–8 Studies with tumor cells in culture suggest that intact checkpoint controls, in the form of cyclin-dependent kinase inhibitors, confer resistance to therapy through cell cycle arrest which prevents replication of damaged DNA in S phase and/or perpetuation of replication errors in unregulated mitosis.3–6
"Protection" conferred by proteins regulating checkpoints presumably reflects the ability of arrested cells to repair therapy-induced damage of DNA, sparing them from apoptosis.3 These observations form the basis for the emerging paradigm of cell cycle-mediated drug resistance and suggest that, under the appropriate circumstances, proteins regulating checkpoint progression may serve as negative prognostic markers in patients.3
In the current issue of the Annals, Moore and his colleagues9 explore the prognostic significance of p27 expression in patients with locally advanced rectal tumors following pre-operative combined chemoradiotherapy. In patients with rectal cancer, the expression of p27 in untreated tumor is a favorable prognostic marker associated with prolonged disease-free survival. Unexpectedly, the present study revealed that the median 5-year recurrence-free survival was significantly worse in patients expressing p27 in residual tumors following combined modality therapy, compared to patients who did not express this protein. In contrast, expression of other key proteins regulating the cell cycle, including p21, p53, Ki67, Rb, cyclin D1, and bcl-2, were not associated with prognosis. Moreover, multivariate analysis revealed that expression of p27 was the key independent negative prognostic factor predicting recurrence-free survival in patients receiving combined modality therapy. The authors hypothesize that p27 promotes the survival of rectal cancer cells treated with combination therapy by mediating checkpoint arrest, restricting the progression of cells with therapy-induced DNA damage through the cell cycle, which consequently escape apoptosis. These observations, in conjunction with those from an earlier study in which recurrence-free survival was significantly worse in patients with residual tumors in which p21 expression7 increased following combined modality therapy, suggest that proteins regulating checkpoint progression are critical determinants of cell cycle-mediated drug resistance in rectal cancer patients receiving pre-operative therapy.
The utility of a new prognostic marker is predicated upon its reproducible and reliable association with a disease about which it provides critical information that is not otherwise available which can be utilized to effectively manage patients.10 In that context, several notes of caution are in order with respect to the present work. This is the first report of the prognostic utility of p27 in residual tumor following multimodal therapy in rectal cancer in what the authors admit is a relatively small sample of patients, and the generalizability of those results to larger patient populations awaits confirmation. In addition, beyond the prognostic implications to patients with residual tumors expressing p27 as a group, it is unclear how the p27 status of an individual patient will specifically impact their clinical management. Moreover, it is premature to begin to design adjuvant therapeutic regimens on the basis of the p27 status of residual tumors, presuming that this marker reflects cell cycle-mediated resistance. Indeed, the mechanistic role of p27 in inducing checkpoint arrest resulting in protection of cancer cells from therapy-induced apoptosis has yet to be demonstrated in these tumors. In the context of that mechanism, it is noteworthy that in the present study changes in Ki-67, a marker of cell proliferation, did not reciprocally correlate with expression of p27 in residual tumors from rectal cancer patients, in contrast to results obtained for p21 in those tumors.7 These considerations underscore the need for further molecular studies to determine whether the expression of p27 is mechanistically associated with cell cycle-mediated resistance, rather than a reflection of alternate mechanisms with less relevance to the design of therapeutic regimens.
The foregoing comments notwithstanding, the present observations suggest the utility of p27 expression in residual tumors as a marker of prognosis and support the novel hypothesis that p27 expression in those tumors may predict response to chemoradiotherapy. These studies form the basis for larger clinical trials of the prognostic utility of this marker in the setting of rectal cancer patients receiving multimodal therapy. In addition, they form the foundation for studies examining the relationship between p27 expression, checkpoint arrest, and cell cycle-mediated resistance to therapy. These latter studies will define the utility of p27 expression as a marker to better target individualized therapeutic regimens to patients with rectal cancer.
Received for publication August 21, 2004. Accepted for publication September 22, 2004.
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