Objective Despite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, ‘ultra-low risk’ endometrioid endometrial adenocarcinomas.
Methods We retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. ‘Ultra-low risk’ was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry.
Results A total of 486 patients with ultra-low risk endometrioid endometrial cancers were identified: 14 (2.9%) of 486 patients developed a recurrence. Median follow-up for non-recurrent endometrioid endometrial cancers: 34 (range 12–116) months; for recurrent endometrioid endometrial cancers: 50.5 (range 20–116) months. Patients with recurrent disease were older, had lower body mass index, and were most commonly non-White (p=0.025, p<0.001, and p<0.001, respectively). Other clinical characteristics did not differ. MMR immunohistochemistry was obtained for 211 (43%) tumors: 158 (75%) MMR-proficient and 53 (25%) MMR-deficient. Primary tumors of 9 recurrent and 27 non-recurrent endometrioid endometrial cancers underwent mutational profiling. Most were microsatellite stable (6/9, 67% recurrent; 25/27, 93% non-recurrent). Recurrent PTEN and PIK3CA mutations were present in both groups. Exon 3 CTNNB1 hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44).
Conclusions Patients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.
- endometrial neoplasms
- genital neoplasms, female
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Contributors MS, JM: conception and design; analysis and interpretation of data; drafting of article; revising article critically for important intellectual content; final approval of version to be published; agree to be accountable for all aspects of the work. NF, KAC: analysis and interpretation of data; drafting of article; final approval of version to be published; agree to be accountable for all aspects of the work. SSKL, CS, RAS, KA, EMDS, APMS, ML, GG, PS, NRA-R: interpretation of data; revising article critically; final approval of version to be published; agree to be accountable for all aspects of the work. BW: analysis and interpretation of data; drafting of article; revising article critically for important intellectual content; final approval of version to be published; agrees to be accountable for all aspects of the work.
Funding This study was funded in part through the NIH/NCI Support Grant P30 CA008748. Dr Weigelt is funded in part by the Breast Cancer Research Foundation, Cycle for Survival, and Stand Up to Cancer.
Disclaimer Dr Abu-Rustum reports grants from Stryker/Novadaq, grants from Olympus, grants from GRAIL, 283 outside the submitted work. Dr Cadoo reports other* from Astra Zeneca, other** from Syndax Pharmaceuticals, outside the submitted work. (*Travel, accommodation, meal; institutional support for therapeutic trial; **institutional support for therapeutic trial.) Dr Leitao is an ad hoc consultant for Intuitive Surgical Inc., outside the submitted work. Dr Soslow reports personal fees from Ebix/Oakstone*; personal fees from Cambridge University Press**; personal fees from Springer Publishers**; personal fees from Roche***, outside the submitted work. (*Preparation of recorded lectures; **royalties; ***one lecture.)
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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