Obstetrics & Gynecology:
Improved Survival With an Intact DNA Mismatch Repair System in Endometrial Cancer
Cohn, David E. MD1; Frankel, Wendy L. MD2; Resnick, Kimberly E. MD1; Zanagnolo, Vanna L. MD1; Copeland, Larry J. MD1; Hampel, Heather MS3; Kelbick, Nicole PhD4; Morrison, Carl D. MD, DVM2; Fowler, Jeffrey M. MD1
From the 1Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 2Department of Pathology, 3Department of Medicine, Division of Human Cancer Genetics, and 4Center for Biostatistics, the Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
Corresponding author: David E. Cohn, MD, 320 West 10th Avenue, M-210 Starling Loving Hall, Columbus, OH 43210; e-mail: David.Cohn@osumc.edu.
OBJECTIVE: To correlate survival and surgical-pathologic factors with DNA mismatch repair status in patients with endometrial cancer.
METHODS: Specimens from 336 patients with endometrial cancer were used to create a tissue microarray. Immunohistochemistry with antibodies against the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 were used to stain the tissue microarray. Clinical, pathologic, and survival data were collected and correlated with the immunohistochemistry results.
RESULTS: Mismatch repair deficiency was seen in 29% (84 of 294) of cases. Correlation was noted between lack of expression of MLH1 and an increased risk for lymphvascular space involvement (32% versus 21%, P=.05) and cervical involvement (26% versus 14%, P=.02). Lack of expression of either MLH1 or MSH2 was associated with thinner patients (85% had a body mass index less than 40 versus 73% of patients with normal expression, P=.02), as well as with the absence of a history of previous primary malignancy (0 verus 13 cases [4%], P=.023). The estimated disease-free survival is 88%; despite a small number of recurrences, there was a nonsignificant improvement in disease-free survival in tumors with an intact mismatch repair system (P=.1). Significantly improved disease-free survival was seen in patients with normal MLH1 and MSH2 expression compared with those with abnormal expression (92% versus 81%, P=.035).
CONCLUSION: Defects in DNA mismatch repair in endometrial cancer is correlated with negative prognostic factors and worse progression-free survival (without a difference in overall survival) compared with tumors with an intact mismatch repair system.
LEVEL OF EVIDENCE: II-3
Endometrial cancer is the most common gynecologic malignancy in the United States, with an estimated 41,200 cases expected to be diagnosed in 2006.1 Less than 10% of endometrial cancers arise as a result of a genetic predisposition to the disease due to an inherited deficiency in the DNA mismatch repair system, predominately in the genes MLH1, MSH2, MSH6, and PMS2.2 This defect results in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and a 60% lifetime risk of endometrial cancer.3 Tumors in patients with Lynch syndrome are characterized as having DNA mismatch repair deficiency that leads to microsatellite instability, the phenotypic change that occurs as a result of an inability to repair DNA mismatches that occur normally during replication. Investigation of sporadic endometrial cancers demonstrates that up to 30% of cases have microsatellite instability despite a lack of germline mutation in a DNA mismatch repair gene.4 Microsatellite instability in this population is generally due to hypermethylation of the MLH1 promoter.5
The clinical significance of microsatellite instability in sporadic endometrial cancer is unclear, with some series suggesting a favorable prognosis with microsatellite instability, some noting that microsatellite instability does not influence prognosis, and others demonstrating poor outcomes in patients with tumors with microsatellite instability. Furthermore, microsatellite instability has been correlated with various surgical-pathologic factors in patients with endometrial cancer. We set out to estimate the correlation between DNA mismatch repair gene expression, traditional surgical-pathologic factors, and survival in a large series of comprehensively staged patients with endometrial cancer.
MATERIALS AND METHODS
Human investigations were performed after approval by a local Human Investigations Committee and in accordance with an assurance filed with and approved by the Department of Health and Human Services. After approval from the Institutional Review Board of Ohio State University/James Cancer Hospital, all patients with primary uterine cancer surgically managed by the faculty of the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology at The Ohio State University College of Medicine from January 1997 to July 2003 who had cancer tissue for review were identified from clinical databases. During this study interval, the philosophy regarding the surgical management of women with endometrial cancer was to perform comprehensive surgical staging in patients with apparently uterine-confined endometrial cancer. Patients generally underwent extrafascial or radical hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy. Omitted or incomplete lymphadenectomy occurred at the discretion of the surgeon and usually involved either gross disease outside the uterus or cancer grossly confined to the endometrium with high operative risk. Patients who did not undergo primary surgical treatment at Ohio State were excluded from the study. Data regarding patient demographics, operative findings, pathology data, and survival were recorded from the source data. Although not separately analyzed, the rate of inherited endometrial cancer in this population (as a result of Lynch syndrome, hereditary nonpolyposis colorectal cancer) is extremely low and would not have been expected to influence the results.6 In general, patients undergo surveillance for recurrence with pelvic examination and vaginal cytology every 3 months for 2 years and then every 6 months for the next 3 years. Imaging is not routinely performed during these visits except at the discretion of the attending physician based on clinical indications.
Tissue cores from formalin-fixed, paraffin-embedded donor blocks from 336 unselected patients with primary endometrial cancer were arrayed into a new 35×20 mm recipient paraffin block with a custom-built precision instrument (Beecher Instruments, Silver Spring, MD). Four cores from each block were used to create a tissue microarray of 0.6 mm cores, including tumor specimens as well as controls. This tissue microarray design was incorporated to maximize the immunohistochemistry results, as has been demonstrated in other studies using tissue microarrays in other malignancies.7 Tumor grading was performed according to current International Federation of Gynecology and Obstetrics (FIGO) standards. All cases were reviewed by one of the authors (C.D.M.). The presence of tumor tissue on the arrayed samples was verified with a hematoxylin-eosin–stained section. A tissue microarray of normal menstrual endometrium was also constructed, consisting of 56 proliferative and 49 secretory-phase endometrial samples.
Immunoperoxidase staining was performed on formalin-fixed, paraffin-embedded tissue cut at 4 microns and placed on positively charged slides. Slides were then placed in a 60°C oven for 1 hour, cooled, and then deparaffinized and rehydrated through xylenes and graded ethanol solutions to water. All slides were quenched for 5 minutes in a 3% hydrogen peroxide solution in methanol to block for endogenous peroxidase. Antigen retrieval was performed by a steamer method in which the specimens were placed in a citric acid solution (Target Retrieval Solution, pH 6.1; Dako Cytomation, Carpinteria, CA) for 30 minutes at 94°C using a vegetable steamer. Slides were then placed on a Dako Autostainer for use with immunohistochemistry and stained with MLH1 (clone G168–15, 1:40, BD Pharmingen, San Diego, CA), MSH2 (clone FE11, 1:200, Oncogene Research Products, Cambridge, MA), MSH6 (clone 44, 1:200, Transduction Laboratories, Lexington, KY), and PMS2 (clone SC-618, 1:200, Santa Cruz Biotechnology, Incorporated, Santa Cruz, CA) antibodies. The detection system used was a labeled streptavidin-biotin complex. This method is based on the consecutive application of 1) a primary antibody against the antigen to be localized, 2) biotinylated linking antibody, 3) enzyme conjugated streptavidin, and 4) substrate chromogen (diaminobenzidine). Tissues were avidin and biotin blocked before the application of the biotinylated secondary reagent. Slides were then counterstained in hematoxylin and dehydrated through graded ethanol solutions, and then the coverslip was placed. For antibodies used in this study, a case was considered negative only if all four cores on the tissue microarray were negative (Fig. 1). A single pathologist (W.L.F.) and one other author (either D.E.C. or K.E.R.) reviewed each tissue microarray. Although immunohistochemistry was performed on all specimens with all antibodies, the denominators reported herein relate to the number of specimens with interpretable results. Given that positive and negative staining was seen on each slide for each antibody, other cores on the tissue microarray serve as the positive and negative controls.
As part of a previous study, our group has demonstrated that, compared with the gold standard of genotyping for microsatellite instability, normal expression of both MLH1 and MSH2 on a tissue microarray predicts a tumor being microsatellite stable in 95% of cases. For the present study, mismatch repair deficiency was defined as lack of expression in any of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2.
Descriptive statistics were reported for the epidemiologic and pathologic variables investigated in the patient population. The χ2 or Fisher exact test was used for comparison of individual surgical-pathologic variables and immunohistochemistry expression. Survival curves were generated via the Kaplan-Meier method and compared using the log-rank test. All reported P values have not been adjusted for multiple testing.
The 336 patients with complete surgical-pathologic data and archival tissue used on the tissue microarray make up the sample investigated in this study. The mean age in this group was 62 years (range 17–89), and the mean body mass index (BMI) was 33.5 kg/m2 (range16–77); almost 60% of the patients had a BMI greater than 30, and 25% had a BMI greater than 40 (Table 1). Surgically, comprehensive staging, including retroperitoneal lymphadenectomy, was performed in 89% of patients, and demonstrated 45 of 299 (15%) patients with retroperitoneal lymph node metastasis (Table 1). As expected, the majority of patients had early stage, well-differentiated tumors (Table 1). Of the 304 patients evaluable for immunohistochemistry of the four mismatch repair genes, expression of MLH1 was seen in 76% (230 of 304), MSH2 in 92% (280 of 304), PMS2 in 72% (211 of 294), and MSH6 in 94% (285 of 304) of patients. The expression of both MLH1 and MSH2 was seen in 222 of 304 (73%) patients, and all four mismatch repair proteins in 210 of 294 (71%) patients. Thus, mismatch repair deficiency was seen in 29% (84/294) of cases (Table 2).
Correlation was noted between expression of certain mismatch repair genes and traditional clinical and surgical-pathologic factors (Table 3). In cancers lacking MLH1 expression, there was a significantly increased risk for the negative prognostic factors of lymphvascular space involvement (32% versus 21%, P=.05) and cervical involvement (26% versus 14%, P=.02). Although not statistically significant, there was a correlation between the loss of MLH1 expression and higher grade (P=.07) and stage (P=.09) tumors. Lack of expression of either MLH1 or MSH2 was associated with thinner patients (85% had a BMI less than 40 versus 73% of patients with normal expression, P=.02), as well as with the absence of a history of previous primary malignancy (0 versus 13 cases [4%] of previous malignancy, P=.023).
After a median follow-up of 29 months, the estimated 5-year disease-free survival of the entire population is 88% (95% confidence interval [CI] 83–91%). Despite a small number of recurrences in the entire population (29 of 336, 9%), a significantly improved disease-free survival was seen in patients with normal MLH1 and MSH2 expression compared with those with abnormal expression of either protein (estimated 5-year survival 92% with normal expression versus 81% with abnormal expression, P=.035, Fig. 2) and a nonsignificant improvement in disease-free survival in these women with normal expression of all four mismatch repair genes compared with patients with abnormal expression of any gene (estimated 5-year survival 92% versus 83%, P=.1, Fig. 3). Patterns of recurrence were similar between the groups, with approximately 80% of recurrences occurring locoregionally and the remaining with some component of distant failure (data not shown).
Investigation of the DNA mismatch repair system in this large sample of comprehensively surgically staged patients with primary endometrial cancer demonstrates a higher risk of surgical-pathologic factors associated with a poor prognosis and a higher risk for recurrence in the presence of defects in the DNA mismatch repair system. Overall, this suggests that the ability to recognize and repair DNA mismatches favors improved cancer outcomes in women with endometrial cancer.
These results are interesting, especially in light of the conflicting results provided by previous investigation of the prognostic significance of microsatellite instability in endometrial cancer (Table 4). In general, most studies investigating the role of microsatellite instability have been performed using a variety of methods to define microsatellite instability, most of which did not routinely have retroperitoneal lymphadenectomy as a surgical component of their care. However, Basil et al,8 in a population similar to the one reported herein (including the use of the consensus panel of markers for genotyping and comprehensive staging in over 80% of patients), investigated 229 patients, 30% of whose tumors demonstrated microsatellite instability. In their series, microsatellite instability did not have any effect on overall or disease-free survival (approximately 75% 5-year overall survival in the overall group). Contrary to our findings, Maxwell et al9 reported a series of 131 patients in which 22% had microsatellite instability. Defective mismatch repair was demonstrated to be associated with an improved survival compared with microsatellite stable tumors. Interestingly, this group reported a 5-year overall survival of only 48% in those patients with microsatellite stable tumors, compared with 77% in patients with tumors with microsatellite instability. The reason for this low survival in the overall group, and in particular in patients with tumors without microsatellite instability, is uncertain, although this may represent a selection bias, in that only 44% of their patients were stage I or II, compared with more than 75% in most other series. Furthermore, it is unclear whether surgical staging with retroperitoneal lymphadenectomy was performed.
Numerous other smaller studies have been performed to determine the prognostic significance of microsatellite instability in patients with endometrial cancer (Table 4), some of which demonstrated more favorable survival with microsatellite instability,10 some of which demonstrated no difference in survival,11,12 and others that demonstrated a worsened prognosis with microsatellite instability.13,14 The reasons for these differing results may again include inadequate sample size and a variable definition of microsatellite instability (leading to ranges in the reported rates of microsatellite instability from 17% to 46%). Lymphadenectomy itself has been identified to provide a survival advantage for patients with endometrial cancer,15 and as such, elimination of this procedure in populations being evaluated for the prognostic significance of microsatellite instability would lead to confusing results. Interestingly, our 5-year disease-free survival of 88% is significantly higher than that reported in most other series. Again, this may reflect accurate assignment of surgical stage by virtue of performing routine comprehensive pelvic and para-aortic lymphadenectomy or a survival advantage afforded by lymphadenectomy itself. Although we report our experience with patients with both endometrioid and nonendometrioid histologies, when we excluded the patients with clear cell and serous carcinomas and carcinosarcomas, no change in the results was noted. As such, it does not seem that the inclusion of nonendometrioid cases influenced these results.
Furthermore, the definition of microsatellite instability has evolved considerably over the last decade. Only recently has there been a consensus as to the appropriate markers to use and the number of these markers that demonstrate instability to document microsatellite instability in a malignancy.16 Deviation from the consensus panel of microsatellite instability markers makes comparisons of studies investigating the significance of microsatellite instability challenging (Table 4). However, the consensus panel of markers was established for the evaluation of microsatellite instability in colorectal cancers. The different instability profiles between colorectal and endometrial cancers may make it challenging to interpret the clinical implications of microsatellite instability status in endometrial cancers using genotyping with the consensus panel of markers.17 In our study, the use of immunohistochemistry for mismatch repair gene expression in the entire group of 336 patients bypasses the use of genotyping and directly evaluates mismatch repair protein expression. Given the high correlation between microsatellite instability (by genotyping) and mismatch repair defects (by immunohistochemistry), we believe that mismatch repair protein expression is both feasible and reliable in evaluation of mismatch repair status in endometrial cancer. However, we acknowledge the evolving nature of the definition of mismatch repair status by immunohistochemistry in endometrial cancer and await continued investigation of mismatch repair by means other than genotyping.
Our study is limited, however, by the fact that data regarding adjuvant therapy for endometrial cancer metastatic to extrauterine sites is not reported. Due to the broad range of adjuvant treatment given for these patients (in general, no therapy for stage I or II cases and either chemotherapy or radiation or chemotherapy and radiation for stage III and IV cases), our study was not powered to evaluate the influence of adjuvant therapy on outcome in this population. However, if as has been reported in colorectal cancer, microsatellite instability in endometrial cancer predicts an improved response to chemotherapy,18 then our conclusions may be confounded by differential responses to adjuvant therapy in the microsatellite stable and microsatellite instability groups. In a subset of patients with nonendometrioid histologies receiving either adjuvant chemotherapy or radiation, we have demonstrated that there is no difference in response to treatment based on mismatch repair status (Resnick KE, Frankel WD, Morrison CD, Fowler JM, Copeland LJ, Kim KH, et al. An intact DNA mismatch repair system does not influence response to treatment with adjuvant chemotherapy or radiation in uterine cancer: A tissue microarray study in surgically staged patients [abstract]. Proc Soc Gynecol Oncol 2006). Our finding that patients with absent MLH1 or MSH2 expression were thinner than those with normal DNA mismatch repair protein expression is consistent with previous data. However, the determination that patients with abnormal MLH1 or MSH2 expression less frequently had been diagnosed with a prior malignancy is interesting and not previously described. It might be assumed that women with endometrial cancer and aberrant DNA mismatch repair protein expression are more likely to have Lynch syndrome and, therefore, to be at higher risk for a diagnosis of colorectal and other malignancies. Thus, the finding of more frequent antecedent malignancies in patients with endometrial cancer and normal expression is surprising and deserves further investigation.
The fact that inconsistent results have been reported for the prognostic significance of microsatellite instability in endometrial cancer differs strongly from results of a recent meta-analysis of the significance of microsatellite instability in colorectal cancer.19 Here, Popat et al demonstrated a 35% improved overall survival in patients with colorectal cancer characterized by microsatellite instability in review of 32 studies that reported survival in 7,642 cases, 1,277 (17%) of which had microsatellite instability. The reasons for the discrepancy between the prognostic significance of microsatellite instability in colorectal and endometrial cancers is unclear but, again, may represent lack of uniformity in the definition of microsatellite instability and the clinical management of patients with endometrial cancer relative to colorectal cancer. However, differences in the biologic significance of microsatellite instability in these tumor types may influence the prognostic significance of mismatch repair because previous studies have demonstrated that microsatellite instability–related target gene mutations in colorectal and endometrial cancers are tissue-specific.20 Specifically, whereas mutations in the TGFβRII gene have been reported in over 90% of colorectal cancers with DNA mismatch repair,21 mutations in this gene are not seen in endometrial cancers with the microsatellite instability phenotype.22 As such, the clinical implications of microsatellite instability in endometrial cancers may differ from that in colorectal cancer due to an alternative pathway to tumorigenesis in endometrial cancers with defective DNA mismatch repair.
From the data reported in this series, we demonstrate a higher risk of surgical-pathologic factors associated with a poor prognosis and a higher risk for recurrence in the presence of defects in the DNA mismatch repair system, suggesting that the ability to recognize and repair DNA mismatches leads to more favorable outcomes in women with endometrial cancer. Currently, the assignment of adjuvant therapy after surgical staging is based on “traditional” surgical and pathologic factors,23 such as the presence of extrauterine disease or high-risk intrauterine factors, eg, cervical or deep myometrial invasion. It is our hope that, through the investigation of molecular surrogates for disease recurrence and survival (such as mismatch repair gene expression and microsatellite instability phenotype), improved treatment, outcome, and quality of life will result for women with endometrial cancer.
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