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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.095 on November 12, 2004

Annals of Surgical Oncology 11:955-961 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Expression of p27 in Residual Rectal Cancer after Preoperative Chemoradiation Predicts Long-term Outcome

Harvey G. Moore, MD, Jinru Shia, MD, David S. Klimstra, MD, Leyo Ruo, MD, Madhu Mazumdar, PhD, Gary K. Schwartz, MD, Bruce D. Minsky, MD, Leonard Saltz, MD and Jose G. Guillem, MD, MPH

From the Departments of Surgery (HGM, LR, JGG), Pathology (JS, DSK), Epidemiology and Biostatistics (MM), Medicine (GKS, LS), and Radiation Oncology (BDM), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Jose G. Guillem, MD, MPH, 1275 York Avenue, Room C-1077, New York, NY 10021; Fax: 646-422-2318; E-mail: guillemj{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Compared with surgery alone, preoperative radiotherapy and 5-fluorouracil–based chemotherapy (combined-modality therapy; CMT) improves outcomes in patients with locally advanced rectal cancer. Although numerous studies have focused on identifying molecular markers of prognosis in the primary rectal cancer before CMT, our aim was to identify markers of prognosis in residual rectal cancer after preoperative CMT.

Methods: Sixty-seven patients with locally advanced (T3–4 and/or N1) rectal cancer were treated with preoperative radiotherapy (median, 5040 cGy) with or without 5-fluorouracil–based chemotherapy. Residual tumor in the resected specimen, available for 52 patients, was analyzed for tumor-node-metastasis stage, lymphovascular and/or perineural invasion, and immunohistochemical expression of p27, p21, p53, Ki-67, retinoblastoma gene, cyclin D1, and bcl-2. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared by the log-rank test.

Results: With a median follow-up of 69 months, the overall 5-year RFS was 74%. RFS was significantly worse for patients with positive p27 expression (P = .005), T3–4 tumors (P = .02), and positive lymph nodes (P = .04) in the irradiated specimen. On multivariate analysis, positive p27 expression remained an independent negative prognostic factor for RFS (P = .04). None of the other proteins was significantly associated with RFS.

Conclusions: Our results indicate that positive p27 expression in rectal cancer after preoperative chemoradiation is an independent negative predictor of RFS. Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered.

Key Words: p27 • Cyclin-dependent kinase inhibitor • Rectal neoplasms • Chemoradiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The addition of radiation and chemotherapy (combined-modality therapy; CMT) to surgical resection is recommended for locally advanced (T3–4 and/or N1–2) rectal cancer.1 Recent evidence suggests that the addition of preoperative radiotherapy (RT) improves the local control of advanced rectal cancer beyond that achieved by optimal surgery (total mesorectal excision) alone.2 However, the subset of patients most likely to experience treatment failure and, therefore, those most likely to benefit from additional or alternative postoperative chemotherapeutic agents remains unclear.

A number of cell cycle–regulatory proteins have been implicated in human carcinogenesis and may be predictors of outcome in human colorectal cancer. p27 is the protein product of a putative tumor-suppressor gene and belongs to the KIP family of nonspecific cyclin-dependent kinase inhibitors (CDKIs) that regulate cell-cycle progression by inhibiting the transition from G1 to S phase.3 p53 is a tumor-suppressor gene involved in the repair of damaged DNA4,5 and promotes apoptosis in part by inhibiting the expression of the antiapoptotic bcl-2 gene.4,5 p53 expression also activates expression of the CDKI p21 (KIP family of CDKIs), which results in cell-cycle arrest in the G1 or G2 phase.6,7 Other regulators of the cell cycle and proliferation—including cyclin D1,8–10 Ki-67,11,12 and the retinoblastoma (Rb) gene12–14—have also been associated with colorectal carcinogenesis.

Low or absent nuclear expression of p27, as assessed by immunohistochemistry (IHC), has been associated with a poor prognosis in a variety of tumors, including breast,15 prostate,16 esophageal,17 lung,18 and bladder3 tumors; cholangiocarcinoma19; and gastric cancer.20,21 In colorectal cancer patients not receiving preoperative CMT, low or absent p27 expression has been found to be an independent predictor of decreased survival in some studies,22–25 but not in others.26,27 Furthermore, preoperative CMT has been shown to alter the expression of p27 and other cell-cycle proteins in the irradiated specimen compared with expression in pre-CMT biopsy specimens.28 However, the prognostic value of p27 expression in residual rectal cancer after preoperative CMT has not previously been reported.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
This retrospective study was reviewed and approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center. During 1987 to 1993, 171 consecutive patients with locally advanced, resectable primary rectal cancer were identified from the Memorial Sloan-Kettering Cancer Center Colorectal Service and Department of Radiation Oncology databases. Of these 171 patients, 34 did not undergo resection or received inadequate doses of radiation (<4500 cGy), and 45 received preoperative treatment at another institution; in another 4, data on preoperative RT were not available. An additional 14 were excluded because they received concurrent intraoperative radiation, and 7 could not be fully evaluated because paraffin blocks were not available for pathologic review. Therefore, 67 patients with potentially curable locally advanced rectal cancer deemed eligible for preoperative CMT because of a bulky and/or tethered tumor or endorectal ultrasound evidence of T3–4 and/or N1 disease were included in this analysis.

All 67 patients received preoperative external beam radiation to the pelvis consisting of at least 4500 cGy delivered over 25 to 26 fractions (180 cGy per day) with a 360-cGy boost to the primary tumor bed, for a total radiation dose of 5040 cGy in 28 fractions, according to previously described techniques.29 Forty patients also received preoperative 5-fluorouracil–based chemotherapy, usually in combination with leucovorin, and 27 received both preoperative and postoperative chemotherapy. Agents and regimens were chosen on the basis of a sequential group of phase I and II trials of concurrent 5-fluorouracil–based chemotherapy. Patients underwent complete resection 4 to 7 weeks after completion of CMT.

Pathologic Analysis
Resected tumor specimens were analyzed for pathologic T (ypT) and N (ypN) stage (after CMT). A pathologic complete response (pCR) was defined as tumors that were ypT0N0. Resected specimens were also analyzed for the presence of "unfavorable features" (lymphovascular and/or perineural invasion).

IHC Analyses
Residual tumor tissue was available for IHC analysis in 52 patients. Thirteen patients had insufficient residual tissue in the resected specimen secondary to a pCR (n = 9) or a near-CR (n = 4). In two patients, tumor blocks were unavailable for IHC staining because of use in another research study. Depending on the amount of residual tissue available, a variable number of proteins were assessed by IHC, ranging from 51 patients with IHC staining for p27 and p53 to 40 patients with staining for Rb, bcl-2, and cyclin D1 (Table 1). In addition, a variable number of patients had a pre-CMT biopsy specimen available for assessment of p27 (n = 27), p53 (n = 27), p21 (n = 26), and Ki-67 (n = 26) expression.


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  		TABLE 1. Molecular expression profiles in resected, irradiated rectal cancer specimens
 
IHC Staining
A standard avidin-biotinylated peroxidase complex technique was used for IHC stains. Briefly, 4-µm sections of formalin-fixed and paraffin-embedded tissue were deparaffinized and rehydrated in graded alcohols. All sections were then subjected to antigen retrieval by microwave oven treatment for 15 minutes in .01 mM citrate buffer at pH 6.0. For Ki-67 antibody, an additional step of incubation was performed in preheated .05% trypsin and .05% CaCl2 in Tris-HCl (pH 7.6) for 5 minutes at 37°C before microwave treatment. The slides were subsequently incubated in 10% normal horse serum for 30 minutes and then in appropriately diluted primary antibodies overnight at 4°C. The antibodies used were p53 (Ab-2, clone 1801, 1/500; Calbiochem, Cambridge, MA), p21 (Ab-1, clone EA10, 1/100; Calbiochem), cyclin D1 (Ab-3, clone DCS-6, 1/100; Calbiochem), p27 (Ab-2, clone DCS72, 1/500; Oncogene Research Products, Cambridge, MA), Ki-67 (Mib-1, 1/50; Immunotech, Marseille, France), Rb (monoclonal antibody, 1/200; Oncogene Science, Boston, MA), and Bcl-2 (clone 124, 1/72; Dako, Glostrup, Denmark). All sections were then incubated with biotinylated anti-mouse immunoglobulin at 1/500 dilution (Vector Laboratories, Inc., Burlingame, CA), followed by avidin-biotin peroxidase complexes (1/25; Vector Laboratories) for 30 minutes. Diaminobenzidine was used as the chromogen, and hematoxylin was used as the nuclear counterstain. Appropriate positive and negative controls were used for each antibody.

IHC Scoring
Interpretation of IHC staining was performed by a single pathologist who was unaware of the patient’s clinical outcome. The percentage of positively stained tumor cells and the intensity of the staining were recorded for all markers. For both post-CMT resection specimens and pre-CMT biopsy specimens, the cutoff values for tumor cell staining were defined as follows: nuclear p27 positivity if >10% of tumor nuclei stained or cytoplasmic p27 positivity if >10% of cells had cytoplasmic staining; p53 overexpression if 5% to 50% of tumor nuclei stained with strong intensity or if >50% stained with any intensity; p21 positivity if >10% of nuclei stained with strong intensity or >30% of nuclei stained with any intensity; high Ki-67 proliferative index if ≥10% of tumor nuclei stained with strong intensity or if >50% of tumor nuclei stained with any intensity; Rb positivity if ≥10% of tumor nuclei stained; Bcl-2 overexpression if >30% of tumor cells showed cytoplasmic staining with any intensity; and cyclin D1 overexpression if >5% of tumor nuclei stained with strong intensity or if >10% of tumor nuclei stained with any intensity. For univariate analysis, tumors were dichotomized into two categories: (1) negative expression (neoplasms below defined cutoff values of immunoreactivity) and (2) positive expression (neoplasms above defined cutoff values of immunoreactivity).

Statistical Analysis
Recurrence-free survival (RFS) distributions were determined by the Kaplan-Meier method30 and compared with the log-rank test.31 Time to last follow-up, treatment failure, or death was measured from the date of surgery. Multivariate analysis was performed with the Cox proportional hazards model.32 P < .05 was considered statistically significant. Comparisons of proportions were performed by using Fisher’s exact test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean age of the patient population was 55 years (range, 24–81 years), with a male predominance (69%). A pCR occurred in 9 (13%) of 67 patients. In the 52 patients with residual tumor available for analysis, the 5-year RFS was 74% at a median follow-up of 69 months (range, 28–138 months). At the time of the most recent follow-up, recurrence had occurred in 13 (35%) of 52 patients, including 4 with local recurrence only, 8 with distant recurrence only, and 1 with local and distant recurrence. Twelve of 13 recurrences were confirmed histologically; the remaining recurrence was based on clinical and radiological follow-up. On the basis of analysis of the resected, irradiated specimen, there were 36 (69%) node-negative and 16 (31%) node-positive tumors. Five tumors (10%) had unfavorable pathologic features. There were 18 T1–2 and 34 T3–4 tumors.

IHC Expression of Cell Cycle–Related Proteins
Results of protein expression in residual rectal cancer after preoperative CMT are given in Table 1. Of note, 6 (12%) of 51 patients were noted to have cytoplasmic staining for p27, including 5 patients with negative p27 nuclear staining and 1 patient with positive nuclear staining for p27.

Differences in IHC Protein Expression Before and After Preoperative CMT
A total of 16 patients had IHC for p27 expression in both a pre-CMT biopsy specimen and in the resected, irradiated specimen (Table 2). The expression status (positive or negative) of p27 before and after CMT was unchanged in 10 patients (63%). Expression was increased in the resected specimen relative to pre-CMT biopsy in three patients (19%) and was decreased in three (19%). The expression status between the pre-CMT biopsy and resected specimen was unchanged in 15 (94%) of 16 cases for p53, 10 (71%) of 14 cases for p21, and 8 (57%) of 14 cases for Ki-67 (Table 2).


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  		TABLE 2. Change in protein expression level: pre-CMT biopsy specimen versus post-CMT expression
 
Univariate Analysis
Results for the univariate analysis are summarized in Table 3. Patients with positive p27 expression had a significantly worse 5-year RFS than patients with negative p27 expression (37% vs. 86%; P = .005; Fig. 1). Patients with involved lymph nodes and T3–4 tumors after CMT had a poorer 5-year RFS than patients with node-negative (56% vs. 82%; P = .04) and T1–2 (61% vs. 94%; P = .02) tumors (Figs. 2 and 3Go). There were trends toward decreased RFS in patients with negative p53 expression and with unfavorable pathologic features (P = .05 and .07, respectively; Fig. 4). There was also a trend toward improved RFS in patients with a pCR (n = 9), but this did not reach statistical significance (P = .11). No significant relationship was seen between expression of the other proteins studied and RFS.


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  		TABLE 3. Univariate analysis for RFS
 


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  		FIG. 1. Influence of p27 expression on recurrence-free survival (RFS). Patients with positive p27 expression in the irradiated, resected specimen had significantly worse RFS than patients with negative p27 expression (P = .005).

 


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  		FIG. 2. Influence of nodal status on recurrence-free survival (RFS). Patients with involved lymph nodes in the irradiated, resected specimen had significantly worse RFS than patients without involved lymph nodes (P = .04).

 


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  		FIG. 3. Influence of pathologic T stage on recurrence-free survival (RFS). Patients with T3–4 tumors had significantly worse RFS than patients with T1–2 tumors (P = .02).

 


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  		FIG. 4. Influence of p53 expression on recurrence-free survival (RFS). Patients with positive p53 expression in the irradiated, resected specimen had improved RFS compared with patients with negative p53 expression (P = .05).

 
Multivariate Analysis
Variables with a P value of ≤.05 on univariate analysis were entered into a multivariate analysis (Table 4). Only positive p27 expression emerged as an independent predictor of poor RFS (P = .04).


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  		TABLE 4. Multivariate analysis for RFSa
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Data are limited on the prognostic significance of the expression of molecular markers in residual rectal cancer after CMT. In a study of 40 rectal cancer patients receiving preoperative radiation and concomitant tegafur suppositories, increased p21 expression after CMT was found to be an independent predictor of improved 5-year survival (92% vs. 50%). However, no association with p53 expression was found.33 Consistent with these results and those of others,34 we found no significant relationship between the expression of p53 in residual rectal cancer and outcome. We also did not observe a relationship between outcome and expression of p21, bcl-2, cyclin D1, Ki-67, or Rb.

Although the expression pattern of p27 in irradiated rectal cancer specimens has previously been reported,28 we are not aware of any prior studies addressing the long-term prognostic significance of p27 expression after CMT. Our findings, demonstrating that expression of p27 in residual rectal cancer after CMT is an independent negative predictor of RFS, are seemingly paradoxical in that increased nuclear p27 expression has previously been associated with improved survival or a decreased incidence of positive lymph nodes and metastatic disease in most colorectal cancer studies.22–25,35,36 However, these and other conflicting studies26,37 have exclusively involved patients not receiving preoperative chemoradiation.

Findings consistent with ours have recently been reported in a series of rectal cancer patients receiving preoperative CMT with or without hyperthermia. In that study, the induction (increased expression in the irradiated specimen compared with the pre-CMT biopsy specimen) of p21 expression, as well as the suppression of Ki-67 expression, was associated with significantly decreased 5-year disease-free survival.34 Although limited by the lack of a multivariate analysis to exclude confounding by other established prognostic factors, these findings are consistent with the emerging concept of cell cycle–mediated resistance to DNA-damaging agents.38,39

In cells with intact cell-cycle control, DNA damage induces arrest at G1 or G2 (mediated, in part, by p21 and p27), followed by the initiation of DNA repair mechanisms. This potentially results in resistance to therapy. In the absence of an intact checkpoint control, DNA repair does not occur, and damaged cells proceed to S phase with an accumulation of replication errors (due to defective G1/S control), uncoordinated mitosis (due to defective G2/M control), or both, with resulting apoptosis. Thus, downregulation or inhibition of CDKIs with consequent disruption of checkpoint control may sensitize cells to DNA-damaging agents.

In support of this concept are preclinical studies involving both p21 and p27. Radiosensitization has been observed in Hct116 human colon carcinoma cells treated with p21 antisense oligodeoxynucleotides.40 Similarly, radiosensitization41 and chemosensitization41–43 have been observed in several carcinoma cell lines treated with antisense p27 oligonucleotide. Furthermore, p21-deficient (p21–/–) Hct116 colorectal cancer cells treated with SN-38 (the active metabolite of irinotecan)44 or gamma irradiation45 demonstrate markedly increased apoptosis compared with similarly treated p21-intact cells.

We found marked differences between p27 expression on pre-CMT biopsy specimens and that in resected, irradiated specimens. In the only other study directly comparing rectal cancer p27 expression before and after chemoradiation, increased expression in the irradiated specimen was found in 11%, and decreased expression was observed in 16%.28

Positive cytoplasmic p27 staining was observed in six patients (12%). Prior studies have noted cytoplasmic p27 expression in 23% to 71% of patients with nonirradiated rectal cancers.27,46 Subcellular localization of p27 to the nucleus, where the main cell cycle–regulatory function occurs, depends on a balance between nuclear import and export. A previous study of nonirradiated rectal cancer patients reported an association between strong cytoplasmic p27 expression and both a decreased disease-free survival and an increased incidence of distant metastatic disease.46 Of the six patients with positive cytoplasmic p27 staining in our study, two had disease recurrence (one local and one distant) during the study period, and four remained recurrence free.

Several limitations of this study deserve comment. First, our sample size of 52 patients may not be adequate. In fact, because an increase in p27 expression between pre- and post-CMT specimens was noted in only three patients, we are unable to comment on the prognostic significance of a dynamic change (induction) of p27 expression. However, our finding of a significant relationship between positive p27 expression after CMT and poor prognosis seems to be consistent with the phenomenon of cell cycle–mediated resistance to therapy. Second, the cutoff values for positive and negative protein expression are derived from the distribution of expression in the current data set, because no standardized values exist, particularly for expression after CMT. Larger-scale prospective studies will be necessary to confirm these findings and validate the cutoff values used in this study. Finally, we were able to assess the expression of p27 and other proteins only in patients with sufficient residual tumor at the conclusion of preoperative chemoradiation. Thus, the prognostically favorable group of patients with pCR are not represented in the analysis, and it is unclear what potential bias this may have had on the results. However, this limitation was unavoidable.

The pharmacological disruption of cell-cycle checkpoint control is an exciting new avenue for research aimed at increasing the response to CMT in patients with locally advanced rectal cancer. Recent studies at our institution have demonstrated the ability of flavopiridol, a CDKI, to increase the apoptotic response to SN-3844 or gamma irradiation45 in Hct116 xenografts when given in sequence after DNA-damaging therapy. This effect seems to be mediated, in part, by inhibition of p21 expression and by direct activation of caspase 3. Results of a phase I trial at Memorial Sloan-Kettering, in which patients with a variety of advanced solid tumors (including esophageal and gastric tumors) received paclitaxel followed by flavopiridol, are encouraging,47 and a phase I trial of sequential gamma irradiation and flavopiridol for unresectable pancreatic cancer is under way. Furthermore, a recently identified gene expressed in Hct116 cells, Drg1, is inducible by SN-38 and subsequently suppressed by flavopiridol therapy. Expression of this gene seems to influence the progression from G2 arrest to apoptosis and is a potential target for colorectal cancer therapy.48

In conclusion, despite modulation of p27 expression in the resected specimen relative to the pre-CMT biopsy specimen, positive p27 expression emerged as an independent predictor of poor RFS. Positive expression of p27 in the residual rectal cancer may, therefore, identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches, such as alternative chemotherapeutic agents, should be strongly considered. Large-scale prospective studies are necessary to confirm the ability of p27 expression in residual tumor after preoperative chemoradiation to predict long-term outcome. Therapies directed at disruption of cell-cycle checkpoint control, such as flavopiridol, may ultimately increase the rectal cancer response to CMT, with consequent improvement in long-term outcome.


   ACKNOWLEDGMENTS
 
Supported in part by National Cancer Institute grant R01 CA82534-01 (J.G.G.). The authors thank Irina Linkov and Marina Asherova of the Core Immunohistochemical Laboratory of the Department of Pathology, Memorial Sloan-Kettering Cancer Center, for their excellent technical support.


   FOOTNOTES
 
Presented at the 56th Annual Cancer Symposium, Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.

Compared with surgery alone, preoperative chemoradiation improves outcome in patients with rectal cancer. Our results indicate that positive p27 expression in the irradiated rectal cancer may identify patients with disease refractory to standard therapy and for whom investigational approaches should be considered.

Received for publication March 24, 2004. Accepted for publication August 1, 2004.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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