Are mismatch repair deficient endometrial cancer recurrences more salvageable than intact cohort? (272)

Objectives: Approximately 25-40% of endometrial cancers (EC) demonstrate deficient DNA mismatch repair (MMRd). MMRd ECs have distinct tumor characteristics compared to MMR intact (MMRi) cohort with higher grade propensity for lymphovascular invasion and frequent lymph node involvement. Despite the worse tumor characteristics, PORTEC-3 data and smaller in vitro studies suggest increased radiosensitivity in MMRd EC. The study aimed to compare the recurrence patterns between MMRd and MMRi EC and assess whether the use of radiation in recurrent settings leads to higher salvage in the MMRd group. Methods: Cases of newly diagnosed EC of all stages and histology were prospectively recruited from three cancer centers in Ontario, Canada, between 2015-2018. All cases were treated with surgery followed by adjuvant treatment. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinical-pathologic, survival, and recurrence details were compared between the MMRd and MMRi cases. Results: Of 666 with EC, there were 83 (12%) recurrences, with 26 (31%; n=83) in MMRd and 57 (69%; n=83) in MMRi cohort after a median follow-up of 26 (2-60) months. There were 503 endometrioid EC, with 148 (29%) MMRd and 355 (71%) MMRi. Restricting the analysis to endometrioid histology only, there were 50 (13%; n=377) recurrences, with 23 (46%; n=50) in MMRd and 27 (54%; n=50) in MMRi cohort. There were no differences in their original stage (p=0.264), grade distributions (p=1.000), rate of lymphovascular space invasion (p=1.000), or type of adjuvant therapy used (p=0.374). Isolated vaginal/pelvic recurrences were more common in the MMRd than MMRi cohort (65% vs 30%), whereas distant recurrences were more common in MMRi cohort (70% vs 35%) (p=0.022). Similar proportion received further treatment for the recurrences (87% vs 81%; p=0.711). Post-recurrence survival (PRS; overall survival after recurrence) was higher in MMRd cohort (median PRS: 43.8 [23.4-53.7] vs 20 [8.1-102.3]; log-rank p=0.306). Of those who had local vaginal/pelvic recurrences, RT with curative intent was used in the majority (9 of 15 in MMRd and 7 of 8 in MMRi) in both groups. All those with local recurrences with MMRd tumors salvaged with curative-intent RT are alive without disease (9 of 9), whereas only two with MMRi tumors are alive without disease (2 of 7). Conclusions: MMRd endometrioid ECs are more likely to recur isolated in the vagina or pelvis than MMRi ECs. Once locoregional recurrence occurs in either MMRd or MMRi EC, curative-intent RT is more likely to salvage the MMRd EC, possibly indicating the increased radiosensitivity in this cohort. Objectives: Approximately 25-40% of endometrial cancers (EC) demonstrate deficient DNA mismatch repair (MMRd). MMRd ECs have distinct tumor characteristics compared to MMR intact (MMRi) cohort with higher grade propensity for lymphovascular invasion and frequent lymph node involvement. Despite the worse tumor characteristics, PORTEC-3 data and smaller in vitro studies suggest increased radiosensitivity in MMRd EC. The study aimed to compare the recurrence patterns between MMRd and MMRi EC and assess whether the use of radiation in recurrent settings leads to higher salvage in the MMRd group. Methods: Cases of newly diagnosed EC of all stages and histology were prospectively recruited from three cancer centers in Ontario, Canada, between 2015-2018. All cases were treated with surgery followed by adjuvant treatment. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinical-pathologic, survival, and recurrence details were compared between the MMRd and MMRi cases. Results: Of 666 with EC, there were 83 (12%) recurrences, with 26 (31%; n=83) in MMRd and 57 (69%; n=83) in MMRi cohort after a median follow-up of 26 (2-60) months. There were 503 endometrioid EC, with 148 (29%) MMRd and 355 (71%) MMRi. Restricting the analysis to endometrioid histology only, there were 50 (13%; n=377) recurrences, with 23 (46%; n=50) in MMRd and 27 (54%; n=50) in MMRi cohort. There were no differences in their original stage (p=0.264), grade distributions (p=1.000), rate of lymphovascular space invasion (p=1.000), or type of adjuvant therapy used (p=0.374). Isolated vaginal/pelvic recurrences were more common in the MMRd than MMRi cohort (65% vs 30%), whereas distant recurrences were more common in MMRi cohort (70% vs 35%) (p=0.022). Similar proportion received further treatment for the recurrences (87% vs 81%; p=0.711). Post-recurrence survival (PRS; overall survival after recurrence) was higher in MMRd cohort (median PRS: 43.8 [23.4-53.7] vs 20 [8.1-102.3]; log-rank p=0.306). Of those who had local vaginal/pelvic recurrences, RT with curative intent was used in the majority (9 of 15 in MMRd and 7 of 8 in MMRi) in both groups. All those with local recurrences with MMRd tumors salvaged with curative-intent RT are alive without disease (9 of 9), whereas only two with MMRi tumors are alive without disease (2 of 7). Conclusions: MMRd endometrioid ECs are more likely to recur isolated in the vagina or pelvis than MMRi ECs. Once locoregional recurrence occurs in either MMRd or MMRi EC, curative-intent RT is more likely to salvage the MMRd EC, possibly indicating the increased radiosensitivity in this cohort.