ATR Mutations in Endometrial Cancer: A Window Into the Role of Mismatch Repair Defects

Since the initial identification that defects in mismatch repair (MMR) lead to the phenotype of microsatellite instability (MSI) in colorectal and endometrial cancer in 1993, it has become well recognized that this feature is present in 15% to 20% of colorectal and 20% to 25% of endometrial cancers. In addition, multiple studies have suggested that colorectal tumors with high-level microsatellite instability (MSI-H) have improved prognosis compared to colorectal tumors that are microsatellite stable (MSS). Perhaps more importantly, several of these studies have also suggested that defective MMR is an important biomarker that may be used to predict lack of response to fluorouracil-based chemotherapy regimens. The prognostic and therapeutic implications of MMR defects in endometrial cancer, however, have been less clear. In 2006, Cohn et al evaluated 294 endometrial cancers and demonstrated that tumors with defective MMR, as evidenced by loss of MLH1 or MSH2 expression, had a worse 5-year disease-free survival (81% v 92%; P .035) compared to tumors with normal MLH1 and MSH2 expression. In contrast to these results, in the same year, Black et al, in a cohort of 473 patients with endometrial cancer characterized for MMR defects by MSI testing, reported that MSI-H endometrial cancers had markedly improved disease-free survival (hazard ratio [HR], 0.3; 95% CI, 0.2 to 0.7; P .01) and disease-specific survival (HR, 0.3; 95% CI, 0.1 to 0.9; P .02) compared to MSS endometrial tumors. Most recently, in 2007, Zighelboim et al evaluated survival in a cohort of 446 endometrioid endometrial cancers that were characterized for defective MMR by MSI testing, and saw no difference between MSI-H and MSS endometrial tumors in either disease-free survival (HR, 0.95; 95% CI, 0.55 to 1.64; P .86) or overall survival (HR, 1.01; 95% CI, 0.69 to 1.48; P .96). In this issue of Journal of Clinical Oncology, Zighelboim et al build on their previous work, and provide valuable insights that may have substantial impact on both our understanding of MSI-H endometrial cancer and possible therapeutic targets in this disease. In this report, Zighelboim et al examine a series of 141 MSI-H endometrioid endometrial cancers for mutations in a 10-base mononucleotide repeat in exon 10 of the ATR gene. This gene is a logical one to explore, given its importance in the activation of cell cycle checkpoints in response to DNA damage and its potential increased susceptibility to somatic mutations in the setting of defective mismatch repair, due to the presence of the long mononucleotide repeat in a protein coding exon. Zighelboim et al identified protein truncating mutations in 12 (8.5%) of 141 MSI-H endometrial cancers. The authors also confirmed the work of prior groups and demonstrated no mutations in this A10 mononucleotide repeat in an additional 107 MSS endometrioid endometrial tumors. On multivariate analysis, presence of an ATR mutation was strongly associated with poorer overall survival when compared to the 129 MSI-H endometrial cancers without an ATR mutation (HR, 3.52; 95% CI, 1.45 to 8.57; P .005) as well as when compared to the entire cohort of 236 endometrial cancers without an ATR mutation unselected for MSI status (HR, 3.88; 95% CI, 1.64 to 9.81; P .002). Building on recent data suggesting that tumors with defective ATR may demonstrate enhanced sensitivity to drugs that inhibit DNA synthesis, the authors suggest that knowledge of ATR mutation status may provide a therapeutic opportunity in MSI-H endometrial cancers. There are many strengths of this intriguing study. Zighelboim et al have analyzed one of the largest single institution cohorts of endometrioid endometrial cancers characterized for MSI status. The methods are robust, and the results make a compelling argument that mutations in ATR are strongly associated with prognosis in MSI-H endometrial cancer. As Zighelboim et al also confirm prior reports that mutations in the ATR A10 mononucleotide repeat occur exclusively in MSI-H unstable endometrial tumors, it appears that the authors have identified an issue that affects only a small fraction of the patients with endometrial cancer. This does not, however, decrease the translational relevance of this study. Previously, Zighelboim et al, in a cohort largely overlapping with that in the current report, found that there was no difference in prognosis between MSI-H and MSS endometrial cancer. Given the current results that MSI-H tumors with ATR mutations have markedly worse survival compared to MSI-H tumors that are ATR wild-type, this would suggest that MSI-H tumors that are ATR wild-type might also have an improved prognosis compared to MSS endometrial tumors. While Zighelboim et al did not see such an effect, it was likely underpowered to do so. In addition, the study inclusion criteria potentially excluded patients with MSI-H endometrial tumors most likely to demonstrate an improved outcome. Of the 195 endometrioid tumors available for analysis, the authors excluded patients with synchronous or metachronous cancers. This group, however, includes many patients likely to have a germline defect in MMR associated with Lynch syndrome. In the 2007 report from Zighelboim et al, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 19 JULY 1 2009