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© 2001 American Society for Clinical Oncology MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung CancerByFrom the Lung Cancer Program, Roswell Park Cancer Institute, Buffalo, NY; and Department of Surgery, University of California at Los Angeles, Los Angeles, CA. Address reprint requests to Gerold Bepler, MD, PhD, Thoracic Oncology Program, Moffitt Cancer Center and Research Institute, MRC-MOLONC, 12902 Magnolia Dr, Tampa, FL 33612; email: beplerg{at}moffitt.usf.edu
PURPOSE: Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non–small-cell lung cancer (NSCLC) was studied.
PATIENTS AND METHODS: We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and
RESULTS: Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with CONCLUSION: Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.
NON–SMALL-CELL LUNG cancer (NSCLC) accounts for approximately 80% of all malignant epithelial lung tumors and includes adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, and adenosquamous carcinoma.1 Despite advances in surgical, radiation, and medical treatment, the 5-year survival rate is currently only 15%.2 This rate is higher than the 8% rate reported for the 1960 to 1963 period,3 and it may be explained in part by earlier detection as a result of increased awareness and more sensitive imaging techniques, which may lead to a higher number of lung cancers detected in earlier stages and a longer average survival time after diagnosis.4 The high mortality for lung cancer is likely a result of early metastatic spread, which is exemplified by the pattern of recurrence in patients with stage I disease, ie, a tumor located in one lobe of the lung without clinical or pathologic evidence for lymph node or other organ involvement.5 In this stage of the disease, more than 70% of relapses occur at distant sites.6 Thus, recent therapeutic efforts have been focused on neoadjuvant and adjuvant chemotherapy to reduce the high systemic relapse rate. To guide clinicians in selecting treatment for patients at high risk for relapse, reliable markers predictive of relapse and poor outcome are needed. Several pathologic and biologic parameters potentially predictive of poor survival have been reported. The most promising include microvessel density,7 submicroscopic metastases,8 metabolic activity,9 mutations in oncogenes and tumor suppressor genes,10-15 expression of extracellular matrix proteinases and inhibitors,16 and expression of proteins involved in cellular proliferation.17-22 We have chosen to compare the abilities of a classic proliferation marker, Ki-67, with a new proliferation marker, MCM2, to predict patient survival on the basis of frequency of staining in resected tumors. Ki-67 is frequently expressed in proliferating cells, and it is absent in quiescent cells. Ki-67 is an epitope of a nuclear protein with unknown function detectable by the MIB-1 monoclonal antibody.23 Its role as a prognostic marker of survival for patients with NSCLC is controversial.20,22 MCM2 is one of six members of the family of minichromosome maintenance (MCM) proteins. They were first discovered in yeast and subsequently in murine and human cells.24,25 MCM proteins are components of the prereplicative complex, which binds to replication origins in the G1 phase of the cell cycle and is essential for the initiation of DNA replication.25-27 After initiation of replication, MCM proteins dissociate from the origin, and this prevents a second round of DNA replication from the same origin during the same S phase. These proteins may also be required for unwinding the parental DNA strands during replication fork progression.28 MCM2 is undetectable in quiescent cells and, thus, serves as a specific marker for replication-competent proliferating cells.29 We investigated MCM2 expression in human tissues using immunohistochemistry (IHC).29 Diffuse nuclear staining was detectable in 12 of 12 invasive breast carcinomas, but within normal tissues it was found only in proliferating cells, such as the epidermal basal layer or the germinal center of lymph nodes. Freeman et al30 also found that MCM protein expression is frequent in dysplastic and malignant cells but infrequent within normal tissue. We31 and others32 have observed that anti-MCM2 antibodies stain a higher proportion of cells in premalignant lesions than do anti–Ki-67 antibodies. This difference suggests that the use of MCM2 antibodies is likely to provide a different, perhaps better, correlation with clinical outcome than the use of anti-Ki-67 antibodies. Here we describe our results in tumors from patients with NSCLC.
Study Population Institutional review board approval was obtained to investigate molecular markers relevant to lung cancer pathogenesis. A total of 1,075 patients were newly diagnosed or had received their first-line treatment for NSCLC at Roswell Park Cancer Institute between June 1995 and September 1999. Of these, 939 were diagnosed with adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, adenosquamous cell carcinoma, or mixed NSCLC. This was the first primary malignancy for 744 patients, and 126 patients did not receive their first-line treatment at Roswell Park Cancer Institute. Of the remaining 618 patients, diagnoses were made by histopathology in 506 and by cytopathology or other means in 112 patients. Staging information was incomplete in 41 patients, and 244 were staged by imaging techniques only. The remaining 221 patients had complete pathologic staging, and their specimen blocks were used for the investigations described here. Data collected included demographics, smoking history (patients who smoked fewer than 100 cigarettes in their lifetime were classified as nonsmokers33), histopathologic diagnosis, grade of differentiation, tumor stage, date of diagnosis, date of death or last follow-up, performance status using the Eastern Cooperative Oncology Group scale (0, no symptoms; 1, minor symptoms; 2, symptoms present, out of bed or chair for more than 50% of the waking hours; 3, symptoms present, in bed or chair for more than 50% of the waking hours), and presence or absence of weight loss at initial presentation (more or less than 5% in 3 months). Tumors were staged pathologically according to the revised international system,5 and they were histologically classified according to the World Health Organization criteria for lung and pleural tumors.34 The median follow-up for all patients was 24.3 months, and the cutoff date for vital status analysis was October 20, 2000.
Specimen Preparation and IHC IHC was done as previously described.29 In brief, sections were deparaffinized and rehydrated. In the case of Ki-67 staining, sections were microwaved twice for 10 minutes in citrate buffer for antigen retrieval. Antigen retrieval was not required for MCM2 staining. An affinity-purified rabbit antiserum raised against the N-terminal region of MCM229 and a mouse monoclonal antibody raised against Ki-67 (clone MIB-1; Immunotech, Inc, Westbrook, ME) were used. The MCM2 antiserum and Ki-67 antibody were used at dilutions of 1/500 and 1/100 respectively. The avidin-biotin detection method was used on a Ventana Automated System (Ventana Medical Systems, Tucson, AZ). An irrelevant rabbit antiserum served as a negative control. The percentage of nuclei stained for both antibodies in cancer cells was recorded by D.-F.T. and confirmed by J.S.J.B.
Statistical Analysis
The average age of the 221 patients was 63.7 years (range, 35 to 88 years). One hundred twenty were men, and 101 were women. Nineteen never smoked, 200 were active or past smokers, and data on cigarette smoking were unavailable for two patients. The distribution of histopathologic diagnoses by pathologic disease stage is provided in Table 1. The performance status was 0 in 137 patients, 1 in 72, 2 in 11, and 3 in one. Thirty-two patients had lost more than 5% of weight in the 3 months before diagnosis, 182 had stable weight, and data were unavailable for seven.
MCM2 immunoreactivity in nuclei of tumor cells or lymphoid cells, which served as internal positive control for a successful stain in specimens with absent tumor staining, was present in 213 specimens and for Ki-67, in 214 specimens. Of these assessable samples, 211 (99.1%) were positive for MCM2 staining in tumor cells, and 206 (96.3%) were positive for Ki-67 (Table 2). Two tumor specimens did not show staining for MCM2, and eight did not stain for Ki-67.
We tested for associations among the categorical variables tumor stage (I, II, III, IV), performance status (0, 1, 2, 3), weight loss (absent, present), histopathology (adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, adenosquamous carcinoma, mixed NSCLC), grade of differentiation (well, moderate, poor), sex (male, female), smoking history (yes, no), and MCM2 and Ki-67 staining (categories 1 to 4) using the  2 test of independence. The percentage of positively stained tumor cells for MCM2 and for Ki-67 was associated (P < .001). The distribution of cases by staining category for MCM2 and Ki-67 is listed in Table 3.
We also noted a statistically significant association between histopathology and MCM2 staining, with fewer positively staining cells in adenocarcinomas compared with squamous cell carcinomas (P < .05, Table 4). All other associations had P values larger than .05.
To test for independent variables significantly associated with survival, we used a step-down Cox regression analysis. The only independent variables significantly associated with survival were tumor stage, performance status, and MCM2 staining category (Table 5). Survival curves, adjusted for tumor stage, performance status, weight loss, sex, histopathology, and smoking history, were plotted for the categories of MCM2 staining, and they are shown in Fig 1A. The survival probability of patients whose tumors had less than 25% cells stained was higher than that of patients whose tumors fell in the other three categories of MCM2 staining, and no difference in survival was observed among these other three categories (Fig 1A). Thus, they were combined and compared with the less than 25% category. Survival curves for these two groups (< 25% v  25% MCM2 staining in tumor cells) are shown in Fig 2A and corroborate the survival advantage for patients in the less than 25% category compared with those in the 25% group (RR, 1.83; 95% CI, 1.13 to 2.96). The median survival time for patients with less than 25% cells positive for MCM2 was 46 months versus 31 months for patients with 25% cells positive for MCM2 (P = .039).
Results from the Cox regression analysis modeled for Ki-67 are summarized in Table 6. Again, tumor stage and performance were independent predictors of survival. The relative risk of death for the staining categories 25% to 49% and 50% to 74% was higher (1.41 and 1.62, respectively) than that for the 0% to 24% reference category, and the relative risk for the 75% to 100% category was 1.14. However, the 95% CIs for these three categories overlapped with the reference category, and the differences observed were not statistically significant. Figure 1B shows the adjusted survival curves for the four Ki-67 staining categories, and Fig 2B shows the survival curves for the less than 25% staining category compared with the combined categories with 25% positively stained tumor cells (Fig 3).
Finally, we explored whether Ki-67 staining added to the information gained from MCM2 staining. Two separate analyses were performed with four combinations (MCM2 < 25% and Ki-67 < 25%, MCM2 < 25% and Ki-67 25%, MCM2 25% and Ki-67 < 25%, and MCM2 25% and Ki-67 25%) and eight combinations (MCM2 < 25% or 25% and each of the four Ki-67 staining categories) of immunostaining. The number of cases in each of these combinations is given in Table 3. There was no significant additional prognostic information obtained by adding Ki-67 staining to MCM2 staining.
MCM2 is a protein with fundamental functions in the replication of eukaryotic cells, and it is required for initiation of DNA replication.25-27 It is absent in cells that have exited from the cell cycle (G0 phase) and present during cellular proliferation in normal cells, premalignant cells, and neoplastic cells.29-31,35 Here we show that the percentage of tumor cells positive for MCM2 is predictive of survival. Patients whose tumors had less than 25% positively stained tumor cells had a significantly longer survival than patients with 25% MCM2-positive cells independent of other clinical and pathologic prognostic parameters of survival. In addition, not all tumor cells had detectable MCM2 by IHC, and two of the 213 specimens assessable for immunostaining had no detectable MCM2 in tumor cells. This suggests (1) that not all malignant cells in a tumor are replication-competent and (2) that the fraction of replication-competent cells is associated with patient survival. Consistent with previous investigations, we found that MCM2 is detectable in nearly all cancers, albeit at different degrees. Out of the 213 NSCLCs studied, two had no detectable MCM2. Lymphoid cells present in both were stained, confirming that the IHC was technically adequate. This was surprising because one would not expect to find a putatively quiescent lung cancer. The first was an adenocarcinoma (Ki-67 negative), which presented as two separate nodules in different lobes of the right lung (stage IV). Because the patient had no other detectable metastatic disease, both lobes were resected. The patient relapsed 28 months later and died as a result of metastatic disease 48 months after diagnosis. The second was also an adenocarcinoma (Ki-67 positive with < 25% tumor cells stained). This cancer was less than 3 cm in size, and there was no evidence for metastatic disease (stage IA). The patient underwent lobectomy and was alive and disease-free 42 months later. This suggests that both tumors were relatively indolent. If MCM2 is essential for cell proliferation, then how can one explain the existence of tumors apparently lacking MCM2? One possibility is suggested by the fact that in the budding yeast Saccharomyces cerevisiae, intracellular concentrations of MCM2 are considerably higher (100-fold to 500-fold) than the number of replication origins,36 and a reduction of MCM2 x 50% had no detectable effect on cellular proliferation, although the efficiency of replication initiation from certain origins was diminished.37 This suggests that proliferating cells, such as lung cancer cells, may have significantly more MCM2 than is required for DNA replication, and a reduction of MCM2 levels below the detection limit of IHC may not necessarily result in quiescence. Another possibility is that, although the tissue section examined by IHC may contain only nonproliferating cells, other portions of the tumor may contain proliferating cells. A third possibility is that the examined tumor may, indeed, have ceased proliferation, but metastatic progeny of such a tumor may remain proliferation-competent.
Of the 211 NSCLCs with positive MCM2 immunostaining, approximately one third had less than 25% of tumor cells stained. This group of patients had a significantly improved survival compared with all others, independent of pathologic tumor stage and other variables thought to be predictive of survival. In light of the marginal benefit derived from chemotherapy for patients with NSCLC, it is tempting to speculate that this group of patients might best be served by a best supportive care intervention once potentially curative strategies are exhausted.38-41 In contrast, the approximately two thirds of patients with MCM2 immunostaining of
We found a significant (P < .001) association between Ki-67 and MCM2 immunostaining. However, as listed in Table 3, these proliferation markers were not coordinately expressed because several specimens in the less than 25% MCM2 staining category expressed Ki-67 to high degrees and vice versa. In addition, the confidence intervals for Ki-67 expression by staining category were large, and consequently staining categories were not significantly correlated with survival. These results are consistent with a study by Mehdi et al20 These authors examined 260 patients with stage I or II NSCLC and reported a median survival of 54 months for patients with
In conclusion, our investigation shows that MCM2 immunoreactivity in malignant cells is an independent and clinically significant prognostic parameter of survival in patients with NSCLC. Patients can be categorized into two subgroups: a prognostically favorable subgroup with less than 25% positively stained tumor cells (comprising approximately 35% of all NSCLC patients), and a prognostically unfavorable subgroup with
Supported in part by a Research Award from the Roswell Park Alliance Foundation, Buffalo, NY (D.-F.T.); grant no. GM49294 from the National Institute of General Medical Sciences, Bethesda, MD (J.A.H.); and a Developmental Funds Award grant no. P30 CA16056-24 from the Roswell Park Cancer Center, Buffalo, NY (G.B.).
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% Ki-67 expression and 45 months for those with more than 25% Ki-67 expression (P = .1). In a second study, increased Ki-67 expression was associated with decreased survival by univariate analysis, but after controlling for other predictors of survival, this association was not statistically significant.
