Original Article
P-Glycoprotein Expression as a Predictor of the Outcome of Therapy for Neuroblastoma
N Engl J Med 1991; 325:1608-1614December 5, 1991
- Abstract
- Abstract
Background and Methods.
Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma.
Results.
P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fisher's exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive.
Conclusions.
Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein—mediated multidrug resistance. (N Engl J Med 1991;325:1608–14.)
Media in This Article
Figure 1
Stage III Adrenal Neuroblastoma Negative for P-Glycoprotein at Diagnosis (Panel A) and Positive (3+) at First Relapse (Panel B).Figure 2
Relapse-free Survival (Panel A) and Overall Survival (Panel B) in 44 Patients with Nonlocalized Neuroblastoma, According to Status for P-Glycoprotein.Article Activity
- Article
MULTIDRUG resistance in chemotherapy for cancer is characterized by increased expression of P-glycoprotein, a conserved 170-kd plasma membrane protein homologous to bacterial-transport proteins.1 , 2 P-glycoprotein is thought to cause cross-resistance to structurally unrelated anticancer drugs by functioning as an ATP-dependent drug-efflux pump of broad specificity.3 4 5 Increased levels of P-glycoprotein or its RNA transcript are found in tumors of epithelial, neurogenic, mesenchymal, and hematopoietic tissues.6 7 8 9 10 11 12 13 Although high levels of P-glycoprotein may be found in cells from many human malignant tumors, it is not clear whether the levels detected are predictive of the duration of response to chemotherapy.14 Previously, in a retrospective study of soft-tissue sarcoma in children, we found a significant correlation between the expression of P-glycoprotein and the outcome of chemotherapy.15 , 16
In the present study, we found a similar correlation between the absence of P-glycoprotein at the time of diagnosis and the curability of advanced neuroblastoma, and between increased expression of the protein and failure of chemotherapy. These findings may have important therapeutic value, since it is now recognized that compounds known as chemosensitizers are able to reverse multidrug resistance in vitro.13 , 17 Neuroblastoma appears to be a good candidate for a trial of the reversal of multidrug resistance by chemosensitizers, because despite increases in the intensity of treatment with chemotherapy, surgery, radiation therapy, and bone marrow transplantation, the survival rate of patients with Stage IV disease is still below 15 percent.18 19 20
Methods
Prognostic Evaluations
We conducted a retrospective study of 67 children with neuroblastoma diagnosed at the Hospital for Sick Children in Toronto from 1964 to 1989. Their records were reviewed, and tumor samples obtained in sequence for clinical reasons were studied. Initial evaluation included computed tomography of the chest, abdomen, and head; radionuclide bone and metaiodobenzylguanidine scanning21; and biopsies of bone marrow and primary and metastatic tumors. The patient's age, tumor stage (according to international staging criteria22), histologic features of the tumor (according to the classification of Shimada et al.23), ratio of urinary vanillyl-mandelic acid to homovanillic acid (VMA:HVA),24 , 25 serum ferritin concentration,26 and tumor N-myc oncogene status27 were the prognostic factors evaluated at the time of diagnosis. Two patients had Stage I tumors (localized to the organ of origin), 21 had Stage II tumors (nodenegative or ipsilateral node-positive tumors beyond the organ of origin), 17 had Stage III tumors (beyond the midline), 19 had Stage IV tumors (distant metastases), and 8 had Stage IVS tumors (limited dissemination to the liver, skin, and bone marrow from a localized primary tumor). The number of N-myc gene copies was determined by Southern hybridization with a 32P-labeled or biotin—deoxyuridine triphosphate—labeled EcoRI—BamHI pNB-1 fragment of human N-myc.27 , 28 Information about neuron-specific enolase,29 tumor karyotype,30 and DNA ploidy31 was not available for analysis.
Treatment Protocols and Assessment of Response
Patients with localized tumors (Stage I or II) were primarily treated with surgery.32 Before 1987, 10 of 23 tumors were also treated with radiation, and 6 with chemotherapy. Chemotherapy was originally used to reduce the tumor burden in patients with nonlocalized tumors (Stage III, IVS, or IV). "Second look" surgery for resection of residual tumor, as well as multiple bone marrow biopsies, was performed to confirm any response. Patients with incompletely resected tumors were treated with radiation.33 Allogeneic or autologous bone marrow transplantation was performed in four patients with Stage IV disease.20 Vincristine, cyclophosphamide, and doxorubicin or dacarbazine were used before 1986,34 and cyclophosphamide, cisplatin, doxorubicin, and teniposide thereafter.18 , 19 Patients with recurrent tumors were treated with alternative chemotherapy, surgery, and radiation. Responses were assessed according to international criteria22 as complete (no measurable disease), partial but very good (a reduction in tumor size of more than 90 percent but less than 100 percent), partial (a reduction of 50 percent or more), or absent (a less-than-partial response or tumor progression). Outcomes were determined in October 1990. Overall relapse-free survival was measured from diagnosis to the last follow-up evaluation, relapse, or death.
P-Glycoprotein Measurement
A previously described multilayer immunoperoxidase method15 , 16 was used to measure P-glycoprotein in 194 formalin-fixed tissue sections and bone marrow samples. Each sample was stained at least three times with two murine monoclonal antibodies, C219 (specific for mdr1 and mdr2/mdr3 genes) and C494 (specific for mdr1 gene).35 , 36 Normal mouse-ascites immunoglobulin G was used as the control. Five multidrug-resistant human ovarian-carcinoma cell lines with 8-, 16-, 64-, 510-, and 1000-fold relative resistance to vincristine, P-glycoprotein—negative SKOV3 cells, and sections of tumor known to be positive or negative were included as controls.15 , 37 The results were interpreted by three observers without knowledge of the patient's response to treatment. The sensitivity of the multilayer method was superior to that of the conventional immunoperoxidase method38 and allowed increased levels of P-glycoprotein to be graded from 1+ to 5+.15 , 16 Samples were scored according to the highest level of P-glycoprotein observed within individual tumor cells.
Statistical Analysis
A good prognosis has been correlated with an age of less than two years, a tumor in Stage I or II, a VMA:HVA ratio of 1 or more, a serum ferritin level of 150 μg per liter or less, favorable histologic features according to the Shimada system, and fewer than three N-myc gene copies; a poor prognosis has been correlated with an age of two years or more, a Stage IV tumor, a VMA:HVA ratio below 1, a serum ferritin level above 150 μg per liter, unfavorable Shimada histologic features, and three or more N-myc gene copies.23 24 25 26 27 Patients with Stage IVS or III tumors have prognoses ranging from moderately favorable to unfavorable.25 , 39 Our 23 patients with localized tumors were negative for P-glycoprotein at diagnosis, and none relapsed or died. They were not included in the analysis of outcome, since chemotherapy would not have influenced their prognosis.32 To evaluate whether P-glycoprotein expression at diagnosis affected the outcome of therapy, the 44 patients with nonlocalized neuroblastoma were divided into two putative prognostic groups, one group positive and one negative for P-glycoprotein.
The response rates of the two groups were compared by the chi-square test and Fisher's exact test. The duration of overall and relapse-free survival was estimated with Kaplan–Meier life tables.40 The patients were further stratified as having a favorable or unfavorable prognosis according to their age, tumor stage, serum ferritin level, histologic features of the tumor, VMA:HVA ratio, and N-myc status, for log-rank analysis of outcome. The proportions of patients in each prognostic subgroup were assessed for uniformity of distribution between the group positive for P-glycoprotein and that negative for P-glycoprotein. Log-rank analysis was used to determine whether each prognostic factor had a significant effect on relapse and death, before and after adjustment for P-glycoprotein expression.41 , 42 Similarly, the effect of P-glycoprotein expression was assessed directly and with adjustment for each prognostic factor and for stage and age together. Two-sided statistical tests were used in all analyses.
Results
Overall, immunohistochemical staining with the antibodies C219 and C494 reproducibly detected no P-glycoprotein in 99 tumor samples, whereas P-glycoprotein was detected in 95 tumor samples. Mouseascites immunoglobulin G control samples were negative. The three observers concurred in their interpretation of samples as positive or negative. Negative samples contained no detectable cells positive for P-glycoprotein, and positive samples contained at least 20 percent. The considerable heterogeneity of P-glycoprotein levels in different types of cells, and of the numbers of positive cells in different tumors, accounted for the differences in the semiquantitative grading in 26 percent of the samples.
P-glycoprotein was not detected in 28 samples of the resected localized tumors of the 23 patients who did not relapse. P-glycoprotein was detected in 22 samples and was absent in 67 samples from the 44 patients who had nonlocalized tumors at diagnosis. Of these 44 patients, 13(12 with Stage IV tumors and 1 with a Stage III tumor) were included in the group positive for P-glycoprotein, and 31 (7 with Stage IV tumors, 16 with Stage III tumors, and 8 with Stage IVS tumors) in the group negative for P-glycoprotein. At follow-up, P-glycoprotein was detected in 49 samples and was absent in 28 samples. The percentage of patients positive for P-glycoprotein at diagnosis was highest among those with Stage IV disease (63 percent), low among those with Stage III disease (6 percent), and zero among those with Stage IVS tumors. The positive tumors originated in the adrenal medulla and abdominal sympathetic ganglia, but not the cervical, mediastinal or pelvic sympathetic ganglia. No increase in P-glycoprotein was found in nonmalignant tissues from all these sites.6 Figure 1Figure 1
Stage III Adrenal Neuroblastoma Negative for P-Glycoprotein at Diagnosis (Panel A) and Positive (3+) at First Relapse (Panel B). shows a tumor that was negative for P-glycoprotein at diagnosis and positive (3+ level) at relapse.The tumors of patients who relapsed changed from being negative for P-glycoprotein to being positive (six patients) (Table 1Table 1
P-Glycoprotein Expression in 44 Patients with Nonlocalized Neuroblastoma (Stages IVS, III, and IV) before and after Treatment.). Successfully treated tumors remained consistently negative for P-glycoprotein, as shown by biopsies during the course of treatment (25 patients). All patients with initially P-glycoprotein—positive tumors except 1 relapsed (12 patients). Heterogeneity of P-glycoprotein expression was observed in every positive tumor. Most positive samples were graded as 1+ or 2 +; only 21 percent were graded as 3+ to 5 +. Eighty-nine percent of the samples were graded as negative or 1 + before treatment, and 56 percent after treatment; the percentage of samples graded as 2+ to 5+ increased from 11 percent before treatment to 44 percent after treatment. Later samples were diffusely positive, and earlier samples more focal. Most regional and metastatic tumors (77 percent) expressed higher levels of P-glycoprotein than the primary tumor. The findings of multiple biopsies performed at the same time usually concurred with respect to the presence or absence of the protein but not the level of expression.The intensity of treatment was comparable in the group that was positive for P-glycoprotein and the group that was negative (Table 2Table 2
Primary Treatment, Response, Outcome, and Survival of 44 Patients with Nonlocalized Neuroblastoma, According to Initial P-Glycoprotein Status and Tumor Stage.). The responses to primary chemotherapy in the patients who were negative for P-glycoprotein were complete in 84 percent of the group and partial or partial but very good in 16 percent. The overall response of this group was superior to that of the patients who were positive for P-glycoprotein; 46 percent of this group had complete responses, 39 percent had partial responses, and 15 percent had no responses (P = 0.014 by chi-square test for all categories of response, and P = 0.0232 by Fisher's exact test comparing the rates of complete response). Responses according to P-glycoprotein status with regard to tumor stage could be compared only in patients with Stage IV tumors, since none of those with Stage IVS tumors and only one of those with Stage III tumors were positive for P-glycoprotein at diagnosis. The most striking feature was the much higher proportion of durable responses in the group that was negative for P-glycoprotein than in the group that was positive: only 6 of 31 in the negative group relapsed, as compared with 12 of 13 in the positive group. The estimated median period of relapse-free survival was not reached in the P-glycoprotein—negative group; in the P-glycoprotein—positive group it was 0.8 year. Of the six patients in the group that was negative for P-glycoprotein who relapsed after treatment, the one with a Stage IV tumor became positive at 1.8 years; the three with Stage III tumors became positive at 0.3, 0.6, and 1.3 years; and the two with Stage IVS tumors became positive at 0.9 and 0.3 year. Of the 12 patients in the group that was positive for P-glycoprotein who relapsed (1 with a Stage III tumor and 11 with Stage IV tumors), all remained positive on evaluation with repeated tumor biopsies. The proportion of patients with prolonged survival was much higher in the group that was negative for P-glycoprotein than in the group that was positive. Only 5 of the 31 patients in the negative group died, as compared with 10 of the 13 patients in the positive group; the median duration of survival was not reached in the negative group, but it was 1.6 years in the positive group. These outcomes are likely to persist because of the prolonged follow-up (a median of 5.5 years in the surviving patients).The probability of overall survival and relapse-free survival in the P-glycoprotein—negative and P-glycoprotein—positive groups are represented by Kaplan–Meier curves in Figure 2Figure 2
Relapse-free Survival (Panel A) and Overall Survival (Panel B) in 44 Patients with Nonlocalized Neuroblastoma, According to Status for P-Glycoprotein.. The actuarial relapse-free survival and overall survival in the group that was negative for P-glycoprotein were significantly superior to survival in the P-glycoprotein—positive group (78 percent vs. 0 percent, P<0.00005 by log-rank test, and 84 percent vs. 14 percent, P = 0.0002 by log-rank test, respectively). When outcome was evaluated in patients with Stage IV disease, who had the poorest prognosis, the group that was negative for P-glycoprotein contained 6 patients with relapse-free survival and 6 of 7 with long-term survival; these figures compared very favorably with those of the group that was positive for P-glycoprotein, which included 1 patient with relapse-free survival and 3 of 12 with long-term survival.Patients with favorable, unfavorable, and unknown prognostic factors (i.e., unknown because of missing data) were fairly uniformly distributed between the groups positive and negative for P-glycoprotein when prognosis was based on age, tumor histology, and VMA: HVA ratio, but they were not uniformly distributed when it was based on tumor stage, serum ferritin concentration, and number of N-myc gene copies (Table 3Table 3
Characteristics at Diagnosis of 44 Patients with Nonlocalized Neuroblastoma (Stages IVS, III, and IV), According to Initial P-Glycoprotein Status.). The relative relapse rates in these subgroups defined according to prognostic factors, including P-glycoprotein status, are shown in Table 4Table 4
Log-Rank Analysis of the Effects on Relapse of Prognostic Factors at Diagnosis in 44 Patients with Nonlocalized Neuroblastoma.. The rates for subgroups based on age, serum ferritin concentration, and VMA:HVA ratio did not differ significantly; these factors did not have a significant effect on relapse before or after log-rank adjustment for confounding by P-glycoprotein status. The relative relapse rates for subgroups defined according to tumor stage and number of N-myc gene copies were significantly different. Tumor stage and N-myc status had a significant effect on relapse (P = 0.0085 and 0.040, respectively) before log-rank adjustment for confounding by P-glycoprotein status, but not after adjustment. The proportion of patients with unfavorable tumor histology was slightly higher in the group that was negative for P-glycoprotein than in the group that was positive, but the relative relapse rates of the patients with unfavorable histologic features were lower than those of the patients with favorable histologic features. The reversed prognostic effect of histology on relapse was significant (P = 0.0011) before log-rank adjustment for confounding by P-glycoprotein status, but not after adjustment. The relative relapse rates of the positive and negative groups were significantly different. P-glycoprotein expression significantly affected relapse (P<0.00005). Thi-s effect remained significant (with the P values shown in Table 4) after individual log-rank adjustments for confounding by age, tumor stage, serum ferritin concentration, VMA:HVA ratio, tumor histology, and N-myc status. Simultaneous stratification was not indicated, since all six prognostic factors had no significant effect on relapse after stratification according to P-glycoprotein status and since the numbers of patients were small. Nevertheless, after elective stratification according to age and tumor stage — reported to be the most important prognostic factors25 — the prognostic effect of P-glycoprotein status on relapse remained statistically significant (P = 0.0011).Log-rank analysis of the effects on mortality of all prognostic factors evaluated at diagnosis was similarly performed. Age (P = 0.67) and N-myc status (P = 0.060) did not have a significant effect on mortality, before or after log-rank adjustment for confounding by P-glycoprotein status. Ferritin concentration (P = 0.032) and tumor stage (P = 0.049) had a significant effect on mortality, but not after log-rank adjustment for confounding by P-glycoprotein status. The prognostic effect of tumor histology on mortality was also the reverse of that expected. This effect was statistically significant both before log-rank adjustment for confounding by P-glycoprotein status (P = 0.0001) and after adjustment (P = 0.001 ). The VMA:HVA ratio had a significant effect on mortality with log-rank adjustment for confounding by P-glycoprotein status (P = 0.027) but not without it (P = 0.103). The effect of P-glycoprotein expression on mortality was significant (P = 0.0002) and remained so after log-rank adjustment for confounding by age, tumor stage, serum ferritin concentration, VMA:HVA ratio, tumor histology, and N-myc status (P = 0.0003, 0.026, 0.0073, 0.0005, 0.010, and 0.0043, respectively). Simultaneous stratification was not indicated, for the following reasons: age, N-myc status, serum ferritin concentration, and tumor stage had no significant effect on mortality after stratification according to P-glycoprotein status; tumor histology had a significant but opposite prognostic effect on mortality; the subgroups of patients defined according to age, tumor histology, and VMA:HVA ratio were fairly uniformly distributed between the groups that were positive and negative for P-glycoprotein; and the numbers of patients were small. Nevertheless, after elective stratification according to age and stage, the effect of P-glycoprotein status on mortality remained statistically significant (P = 0.0373). Thus, P-glycoprotein expression significantly affected the rates of relapse and mortality among patients with neuroblastoma, when log-rank analysis of outcome was stratified according to age and tumor stage.
Discussion
In this study, P-glycoprotein was not detected in localized neuroblastoma but only in neuroblastoma that was nonlocalized at diagnosis. The tumors of all the patients who relapsed after treatment had increased expression of P-glycoprotein. Any detectable level of increased P-glycoprotein was associated with an unfavorable prognosis. Although levels of the protein were higher in regional and metastatic tumors than in primary tumors, and higher at later relapses than at earlier relapses, we did not correlate the magnitude of increase in the P-glycoprotein level with the intensity of chemotherapy. The pretreatment expression of P-glycoprotein was prognostic of the success or failure of therapy in patients with nonlocalized tumors, as shown by the significantly superior rates of response to treatment and of relapse-free and overall survival in the group that was negative for P-glycoprotein as compared with the group that was positive for the protein. The differences between the outcomes in the two groups remained statistically significant after stratification according to age and tumor stage, the two most important reported prognostic factors.25
The multilayer immunohistochemical method employed in this study allowed retrospective analysis of sequential archival tumor samples obtained from each patient during the course of disease.15 , 16 The information on the evolution of P-glycoprotein expression was crucial to the correlation of such expression with the long-term outcome of therapy. Longitudinal studies are thus more valuable than horizontal studies performed at a single point in assessing the prognostic role of P-glycoprotein expression.8 , 9 , 16
These findings raise important questions that merit further study. First, P-glycoprotein was not detected in localized tumors, yet increased levels were observed initially in 63 percent of Stage IV tumors. Does the protein have any marked influence on the biologic aggressiveness and metastatic potential of neuroblastoma? Second, P-glycoprotein was not detected in tumors associated with a good prognosis that originated in the cervical, mediastinal, or pelvic sympathetic ganglia, but it was found in tumors associated with a poor prognosis that arose in the adrenal medulla and abdominal sympathetic ganglia. Are these locations related to the biologic behavior or ontogeny of neuroblastoma? Third, the majority of metastatic lesions expressed higher levels of P-glycoprotein than the primary tumors. Is this a manifestation of adverse biologic behavior or a consequence of the progression of multidrug resistance? Fourth, pretreatment P-glycoprotein expression appeared to be an important predictor of the duration of response to chemotherapy in neuroblastoma and childhood soft-tissue sarcoma.16 Does it have an equally important prognostic role in all neoplasms treated with chemotherapy? The answers to some of these questions have broad implications and may be crucial for understanding the poor outcome of patients with advanced neuroblastoma.
Chemoresistance may be due to a host of biologic and drug-resistance factors, of which multidrug resistance related to P-glycoprotein is the best studied in human tumors.43 In this study, the pretreatment P-glycoprotein expression had a substantial association with the outcome of therapy for nonlocalized neuroblastoma. Although P-glycoprotein expression at diagnosis has considerable prognostic importance, the amount of the protein can change during treatment, and this may have implications for the subsequent outcome of therapy. The complete absence of relapses among patients consistently negative for P-glycoprotein suggests that mechanisms of drug resistance not related to the protein are not important in such patients. This finding has also been made in patients with childhood sarcoma.16 Other mechanisms of drug resistance, such as alterations in DNA topoisomerases or glutathione detoxification, may be acquired in parallel and may be operational in tumors with increased P-glycoprotein expression.43
What are the implications of these findings for therapy? The potential for early identification of multidrug resistance in tumors will be useful in individualizing anticancer therapy. Studies of different types of tumors should be performed, since knowledge about the effect of P-glycoprotein expression on the prognosis of neuroblastoma and childhood sarcoma might not be broadly applicable to all neoplasms treated with chemotherapy. This is an important issue, since chemosensitizers that reverse the phenotype for multidrug resistance in vitro are being tested in clinical trials.13 , 43 These agents may reverse multi-drug resistance in tumors in which the response to chemotherapy is limited by the increased expression of P-glycoprotein.
Supported by grants (to Dr. Chan, Dr. Ling, and Dr. Yeger) from the National Cancer Institute of Canada and by a Public Health Service grant (CA-37130 [to Dr. Ling]) from the National Institutes of Health. Dr. Chan is a Research Scientist of the National Cancer Institute of Canada.
Presented in part at the 81st Annual Meeting of the American Association for Cancer Research, May 23–26, 1990, Washington, D.C.
We are indebted to Drs. M.L. Greenberg, S.S. Weitzman, and H. Solh for allowing us to study their patients.
Source Information
From the Divisions of Hematology—Oncology and Immunology and Cancer, Departments of Pediatrics (H.S.L.C., G.H., Y.P.L.) and Pathology (P.S.T., N.O., H.Y.), Hospital for Sick Children and University of Toronto, and the Department of Biostatistics (G.D.) and Division of Molecular and Structural Biology (V.L.), Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, all in Toronto. Address reprint requests to Dr. Chan at the Division of Hematology—Oncology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1×8, Canada.
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