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© 2000 American Society for Clinical Oncology Reduced MLH1 Expression in Breast Tumors After Primary Chemotherapy Predicts Disease-Free SurvivalFrom the CRC Department of Medical Oncology, Cancer Research Campaign, Beatson Laboratories, Glasgow University; Department Pathology, Stobhill National Health Survey Trust; Beatson Oncology Center, Western Infirmary, Glasgow; and Department Oncology, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; for and on behalf of the Edinburgh Breast Unit. Address reprint requests to Robert Brown, MD, CRC Beatson Laboratories, Glasgow University, Switchback Rd, Glasgow G61 1BD, United Kingdom; email gpma61{at}udcf.gla.ac.uk
PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival. PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively. RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P = .010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P = .0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors. CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.
BREAST CANCER IS the most common malignancy among women in the Western world. The majority of women present with disease localized to the breast with or without axillary lymph node involvement.1 Despite radical surgery, more than 50% of surgically treated patients eventually relapse. The introduction of adjuvant treatment (endocrine, chemo-, and radiotherapy) has resulted in a reduction in mortality, with a 25% survival improvement at 10-year follow-up.2 Metastatic disease, however, remains incurable, with patients becoming progressively less sensitive to systemic therapy. Primary (neoadjuvant) chemotherapy is increasingly being used in the treatment of primary breast cancer. Its effectiveness in inducing tumor regression and, thus, allowing more conservative surgery (particularly avoidance of mastectomy) is well established.3-5 Disease-free and overall patient survival have been correlated with the clinical response to primary chemotherapy, although results have been conflicting.6,7 Studies have failed to predict tumor response to primary chemotherapy using proliferation indices, expression levels of the tumor suppressor gene p53 or the apoptosis inhibitor BCL2, and amplification of the oncogene c-erbB-2.8-10 Data for the MDR1 gene product P-glycoprotein (P-gp) are conflicting,11 although coexistent p53 and P-gp expression has been reported to be an independent prognostic factor for short disease-free survival.12 Overexpression of c-erbB-2 has also been reported as an independent prognostic factor for short disease-free and overall survival,13 although again data are conflicting.9 Several studies have suggested a role for mismatch repair (MMR) deficiency in the development of drug resistance.14-16 Loss of the MMR protein MLH1 occurs in tumor cell lines selected for resistance to methylating agents, cisplatin, and doxorubicin.14,15 The promoter of the hMLH1 gene has recently been shown to undergo hypermethylation in tumors and cisplatin-resistant cell lines, which correlates with loss of MLH1 expression.17,18 This may be the basis for the high frequency of MLH1 loss, rather than other MMR proteins, observed in tumors and drug-resistant models.14-17 MLH1-deficient tumor lines with MMR activity restored by chromosome transfer are more sensitive than the MMR–deficient parental line to several clinically important agents, including cisplatin, carboplatin, doxorubicin, etoposide, and thioguanine.16,19 Exposure to such agents in vitro and in vivo results in enrichment of the MLH1-deficient population.20,21 Loss of MMR leads to an increased rate of frameshift mutations in DNA, which is manifested by genetic instability at repeat sequences in DNA, giving increase to microsatellite instability (MSI).22 Thibodeau et al23 examined paraffin-embedded tissue from colorectal tumors for both MLH1 and MSH2 by immunohistochemistry (IHC) and compared the results with detection of MSI and MMR gene mutation analysis. They showed that loss of immunohistochemical staining for these MMR proteins corresponded closely with loss of function of these genes detected by MSI. Mutation of the tumor suppressor gene p53 is a frequent genetic change in breast cancer.24 Although the results of studies vary, mutant p53 is generally viewed as an indicator of poor prognosis in breast cancer.25,26 In view of the central role of wild type p53 in cell cycle control and induction of apoptosis,27,28 mutation of p53 may play a role in the development of resistance to chemotherapy. An in vitro study examining chemosensitivity in human breast cancer specimens reported a correlation between mutant p53 protein expression and enhanced chemoresistance.29 These findings, however, have not been supported in clinical studies, with mutant p53 failing to act as an indicator of response to chemotherapy.8,9,30 The aim of the present study was to investigate MLH1 and p53 expression in sporadic breast cancer. The study focused on these two proteins because of the limited amount of biopsy material available for analysis, especially before treatment, and previous in vitro studies implicating their importance in drug resistance.16,17,29 Using samples obtained before and after neoadjuvant chemotherapy, we have examined the effect of chemotherapy on MLH1 and p53 expression and have assessed the correlation of these markers with clinical outcome.
Patients Archival paraffin-embedded material was obtained from 36 patients treated with neoadjuvant chemotherapy for primary breast cancer between 1993 and 1997. Samples were obtained from either the Beatson Oncology Center (Glasgow, United Kingdom) or the Western General Hospital (Edinburgh, United Kingdom). Samples consisted of a tru-cut biopsy taken at the time of diagnosis and tumor taken at surgery after chemotherapy. Of the 36 patients, paired samples were available for 29; for seven patients, paired biologic determinants were not available because of the few or no tumor cells present in their samples. Median age of the patients was 47 years (range, 26 to 66 years). The median maximum tumor diameter at diagnosis was 6 cm (range, 2.9 to 15 cm). Other patient characteristics are as listed in Table 1. Eleven patients received continuous-infusion fluorouracil 200 mg/m2/d, doxorubicin 50 mg/m2, and cyclophosphamide 600 mg/m2 every 3 weeks; 16 patients received doxorubicin 20 to 30 mg/m2 /wk and continuous-infusion fluorouracil 200 mg/m2/d; and nine patients received epirubicin 50 mg/m2 and cisplatin 60 mg/m2 three times weekly and continuous-infusion fluorouracil 200 mg/m2/d. All patients completed at least 9 weeks of treatment before the repeat biopsy at surgery. Radiotherapy was administered according to local practice after both chemotherapy and definitive surgery. Those who were estrogen receptor-positive were placed on tamoxifen. Response was assessed by bidimensional tumor measurement, obtained retrospectively from patients’ case records, evaluated according to International Union Against Cancer criteria, and maintained over at least 4 weeks.31 Median follow-up was 41 months (range, 30 to 66 months).
Immunohistochemistry IHC was performed on histology sections taken from the tru-cut biopsy and mastectomy specimens. All samples were formalin-fixed and paraffin-embedded. Mouse monoclonal antibodies G168-15 (1/100 dilution; PharMingen, Oxford, United Kingdom) and DO-1 (1/200 dilution; Oncogene Sciences, Cambridge, United Kingdom) were used to detect MLH1 and p53, respectively, using a peroxidase-labeled streptavidin-biotin technique.32 Slides were deparaffinized in Histoclear (Fischer Scientific Ltd, Loughborough, United Kingdom) then rehydrated through graded alcohols and water. Removal of endogenous peroxidase activity was achieved by incubation in 0.1% hydrogen peroxide for 20 minutes. Sections were immersed in 10 mmol/L sodium tricitrate buffer pH6, subjected to heat-induced antigen retrieval by microwaving for 15 minutes, and then cooled for 20 minutes. The commercially available Vectastain Elite ABC Kit (Vector Laboratories Burlingame, CA) was used to detect the antigen. Sections were lightly counterstained with hematoxylin. Internal controls were obtained for each slide by omitting the primary antibody. For MLH1, external controls included A2780 cells (positive control for MLH1 and negative control for p53) and A2780/CP70 cells (negative control for MLH1 and positive control for p53).14,33 Two slides per patient sample were immunostained in separate runs. Slides were scored by a consultant pathologist using light microscopy. A score of 0 to 3 for stain intensity was assigned: no staining = 0; weakly positive = 1; moderately positive = 2; and strongly positive = 3. Percentage staining was assessed both as a percentage figure and according to the scoring system: 0 = 0% to 5%; 1 = 5% to 20%; 2 = 20% to 80%; and 3 = 80% to 100%. A combined immunohistochemical score (H-score) was achieved by multiplying the percent by the intensity score.34 Both immunostaining and scoring were blinded to clinical outcome.
Statistical Methods
Changes in MLH1 and p53 Expression in Response to Chemotherapy Paired breast tumor samples from the same patient before and after neoadjuvant chemotherapy were evaluated for MLH1 immunohistochemical (IHC) staining. An example of MLH1 immunohistochemical analysis of paired samples before and after chemotherapy is shown in Fig 1. There was a significant reduction in the percent of cells expressing MLH1 after neoadjuvant chemotherapy (P = .010, n = 28). Matched patient percent MLH1 H-scores before and after chemotherapy are shown in Fig 2. The median percent before and after chemotherapy was 83% and 75%, respectively. Furthermore, there was a reduction in the intensity of staining within cells seen after chemotherapy (P = .068, n = 28). Sixty-one percent of patients had immunostain intensity scores of 2 or greater before treatment compared with 36% after chemotherapy. The overall median MLH1 H-score (multiplying percentage and intensity) after chemotherapy was significantly lower than before chemotherapy (P = .036, n = 28). A subgroup analysis by chemotherapy regimen also showed a reduction in median MLH1 after chemotherapy.
There was no statistically significant correlation between percent or intensity of MLH1 and p53 staining before or after chemotherapy. There was no significant difference between the p53 H-scores after chemotherapy. Subgroup analysis of p53 H-scores by individual chemotherapy regimen also failed to show any difference before and after chemotherapy.
Univariate and Multivariate Analysis
Analysis of individual patients with low MLH1 expression (before or after chemotherapy) has shown they have a short disease-free survival. Three patients had completely lost expression of MLH1 after chemotherapy, and they relapsed at 4, 8, and 15 months, respectively. Two patients had significantly low expression of MLH1 before chemotherapy (0% and 10% of cells positive for immunostaining); these patients progressed at 12 months and 6 weeks, respectively. Of the seven patients for whom paired samples were unavailable, one achieved a complete response (prechemotherapy sample 80% MLH1-positive) and remains in remission at 49 months. Of the remaining six patients, no clear pattern emerged and the distribution of prechemotherapy MLH1 scores was indistinguishable from the others. The failure to produce a postchemotherapy MLH1 score was because of poor sample quality. A univariate analysis of clinical characteristics showed an association between poor disease-free survival and young age (P = .001, n = 34), premenopausal status (P = .024, n = 34), and poor response to chemotherapy (P = .005, n = 33). The associations between disease-free survival and estrogen receptor status, nodal stage, tumor grade, and pathologic nodal status after chemotherapy were not statistically significant at the 20% level. A forward stepwise multivariate analysis was conducted using the statistically significant clinical features along with MLH1 intensity, percentage staining, combined IHC score after chemotherapy, and change in IHC score (before and after). This identified percentage staining (P = .019), age (P < .001), response to chemotherapy (P = .001), and menopausal status (P = .041) as independent prognostic factors (n = 27).
Neoadjuvant treatment provides a system to study in vivo the effect of chemotherapy on the proportion of cells expressing given genes in the initial biopsy compared with the tumor after chemotherapy from the same patient. This provides an ideal opportunity to study clinical drug resistance. A small number of studies have examined the impact of neoadjuvant chemotherapy on biologic marker expression, with changes observed in proliferation indices, proliferating cell nuclear antigen, expression of P-gp, and epidermal growth factor receptor.35-37 However, a consistent picture correlating these markers with clinical drug resistance has not yet emerged. There have been numerous in vitro studies linking the loss of DNA MMR to drug resistance,14-16 but little is known about its clinical significance. We have shown, for the first time, that combined chemotherapy results in loss of MLH1 expression, and that this is a poor prognostic indicator in patients receiving neoadjuvant treatment for locally advanced breast cancer. Loss of MLH1 expression seems to act independently of the other prognostic factors in this study and to be a good predictor of poor disease-free survival. These observations are consistent with the hypothesis that tumor cells with reduced MLH1 have a survival advantage during chemotherapy and also support the contention that loss of MLH1 plays a role in drug resistance. MLH1 expression after chemotherapy, but not before chemotherapy, is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer. Expression analysis before chemotherapy may fail to predict disease-free survival because of an inability to identify resistant subpopulations that are more readily identifiable after chemotherapy. This holds the caveat that postchemotherapy biopsy represents residual and not necessarily clinically resistant disease. It is conceivable that, rather than causing drug resistance, loss of MLH1 is a marker for other changes that result in a more aggressive tumor phenotype. However, in vitro studies show that restoration of MMR in deficient cells restores drug sensitivity,16,19 strongly arguing that MMR can have a direct role in drug sensitivity and, therefore, potentially in response of patients to chemotherapy. Acquisition of microsatellite instability phenotype, a marker for loss of MMR, has previously been shown to correlate with reduced survival and poor disease prognosis in breast cancer.38 Conversely, a microsatellite phenotype correlates with good prognosis in colon cancer.39 These differences may reflect the different impact of a mutator phenotype on tumor progression (in the case of colon cancer) versus lack of MMR on drug sensitivity (in the case of breast cancer).
How MMR deficiency could lead to the development of drug resistance is not yet fully understood. The MMR protein MutS We chose to examine MLH1 expression specifically as this is the MMR protein that has been shown in vitro to be most frequently lost as a result of serial exposure to chemotherapy.14 An increase in ovarian tumors immunologically negative for MLH1 is observed in samples taken after chemotherapy compared with untreated tumors.14 The frequent loss of MLH1 may be because of the higher probability of inactivation by methylation of the promoter of this gene.17,18 Patients in the present study received regimens containing either doxorubicin or cisplatin, drugs exhibiting resistance in vitro associated with loss of MLH1 expression.14-17 Consistent with other studies,36 p53 showed no significant prognostic value before or after combination chemotherapy and no significant change in the levels of protein expression. It should be stated, however, that IHC may not be a reliable measure of p53 function, and controversy exists as to its use in determining the value of p53 as a prognostic factor. We could find no association between MLH1 and p53 expression as assessed by IHC. Our results should be viewed with caution because of the relatively small patient numbers, different chemotherapy regimens, and the use of a selected patient population. However, this study does demonstrate, for the first time, clear evidence for loss of MLH1 as a result of chemotherapy in matched pairs of breast tumor samples. Further, it suggests that loss of expression of MLH1 is an important prognostic factor in predicting disease-free survival in this group of patients. Large prospective studies are now necessary to further validate these observations. If loss of MLH1 is confirmed as being involved in clinical drug resistance in breast cancer, this opens up a number of possibilities for improving treatment results, including the development of agents that may be active in MMR-deficient cells or that may be capable of reversal of resistance.
Supported by the Cancer Research Campaign, United Kingdom. We thank Dr. R. Leonard (Edinburgh Breast Unit) and all the surgeons and pathologists in Glasgow and Edinburgh who made samples available.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
(a heterodimer of MSH2 and MSH6) recognizes and binds to sites of DNA damage, such as O6-methylguanine and 1,2-cisplatin intrastrand crosslinks, and is proposed to lead to recruitment of MutL
