Tailoring Therapy in Post-surgical Patients With Low-risk Endometrial Cancer

Inclusion Criteria:

• Patients must have had surgery consisting of hysterectomy (total abdominal,laparoscopic or robotic-assisted) and bilateral salpingo-oophorectomy. Lymph nodedissection can be performed as per institutional standards (sentinel or fulllymphadenectomy). There must be no macroscopic residual disease after surgery

• Patients must have histologically confirmed stage I to III endometrial carcinomawhich can be endometrioid, serous, clear cell, un/dedifferentiated, carcinosarcomaor mixed

• Patients' Eastern Cooperative Group (ECOG) performance status must be 0, 1, or 2

• Patients' age must be >= 18 years

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient must sign a consent form prior toenrollment in the trial to document their willingness to participate. A similarprocess must be followed for sites outside of Canada as per their respectivecooperative group's procedures

• Patient is able (i.e. sufficiently fluent) and willing to complete the patientreported outcomes (PRO) questionnaires in either English, French or a validatedlanguage. The baseline assessment must be completed within required timelines, priorto enrollment. Inability (lack of comprehension in English or French, or otherequivalent reason such as cognitive issues or lack of competency) to complete thequestionnaires will not make the patient ineligible for the study. However, abilitybut unwillingness to complete the questionnaires will make the patient ineligible

• Patients must be accessible for treatment and follow-up. Patients enrolled on thistrial must be treated and followed at the participating centre. This implies theremust be reasonable geographical limits placed on patients being considered for thistrial. The patient's city of residence may be required to verify their geographicalproximity. (Call the CCTG office (613-533-6430) if questions arise regarding theinterpretation of this criterion.) Investigators must assure themselves the patientsenrolled on this trial will be available for complete documentation of thetreatment, adverse events, and follow-up

• Patients must agree to return to their primary care facility for any adverse eventswhich may occur through the course of the trial

• Protocol treatment is to begin within 10 weeks of hysterectomy/bilateralsalpingo-oophorectomy

• SUB-STUDY A: Patients with endometrial carcinoma (endometrioid, serous, clear cell,un-/dedifferentiated, carcinosarcoma, mixed), must have one of the followingcombinations of International Federation of Gynecology and Obstetrics (FIGO) stage,grade, and lymphovascular invasion (LVI):

• Cohort A1:

• Stage IA (not confined to polyp), grade 3, pN0, with or without LVI (Pelvic lymph node surgical assessment (sentinel or full lymphadenectomy)is required for grade 3 or stage II. Para-aortic lymphadenectomy is notmandated.)

• Stage IB, grade 1 or 2, pNx/N0, with or without LVI

• Stage IB, grade 3, pN0, without substantial LVI (Pelvic lymph nodesurgical assessment (sentinel or full lymphadenectomy) is required forgrade 3 or stage II. Para-aortic lymphadenectomy is not mandated.)

• Stage II (microscopic), grade 1 or 2, pN0, without substantial LVI (Pelviclymph node surgical assessment (sentinel or full lymphadenectomy) isrequired for grade 3 or stage II. Para-aortic lymphadenectomy is notmandated.) (Substantial LVI is defined as >= 3 foci per College ofAmerican Pathologists' reporting guideline)

• Cohort A2:

• Stage IA (not confined to polyp), grade 3, pNx, with or without LVI

• Stage IB, grade 3, pNx, with or without LVI

• Stage IB, grade 3, pN0, with substantial LVI (Substantial LVI is definedas >= 3 foci per College of American Pathologists' reporting guideline)

• Stage II (microscopic), grade 1 or 2, pNx, with or without LVI

• Stage II (microscopic), grade 1 or 2, pN0, with substantial LVIƒõ

• Stage II (microscopic), grade 3, pNx/N0, with or without LVI

• Stage II non-microscopic, any grade, pNx/N0, with or without LVI

• Stage III, any grade, pNx/N0-2, with or without LVI

• Substantial LVI is defined as .3 foci per College of AmericanPathologists¡¦ reporting guideline

• SUB-STUDY A: Patients must have a molecular classification of POLE mutation.

• Note: patients in Cohort A2 should have a known POLE pathogenic mutation priorto consenting

• SUB-STUDY B: Patients with endometrial carcinoma (endometrioid only), must have oneof the following combinations of FIGO stage, grade, and lymphovascular invasion (LVI):

• Stage IA (not confined to polyp), grade 3, pN0, with or without LVI (Pelviclymph node surgical assessment [sentinel or full lymphadenectomy] is requiredfor grade 3 or stage II. Para-aortic lymphadenectomy is not mandated) (Substantial LVI is defined as >= 3 foci per College of American Pathologists'reporting guideline)

• Stage IB, grade 1 or 2, pNx/N0, with or without LVI

• Stage IB, grade 3, pN0, without substantial LVI (Pelvic lymph node surgicalassessment [sentinel or full lymphadenectomy] is required for grade 3 or stageII. Para-aortic lymphadenectomy is not mandated) (Substantial LVI is defined as >= 3 foci per College of American Pathologists' reporting guideline)

• Stage II (microscopic), grade 1 or 2, pN0*, without substantial LVI (Pelviclymph node surgical assessment [sentinel or full lymphadenectomy] is requiredfor grade 3 or stage II. Para-aortic lymphadenectomy is not mandated) (Substantial LVI is defined as >= 3 foci per College of American Pathologists'reporting guideline)

• SUB-STUDY B: Patients must have molecular classification of p53wt/NSMP (based onnormal p53 IHC, and absence of pathogenic POLE mutation or MMR deficiency)

• SUB-STUDY B: Estrogen receptor positive (> 10% of the tumour with positive nuclearstaining) on IHC

Exclusion Criteria:

• Prior neoadjuvant chemotherapy for current endometrial cancer diagnosis

• Prior pelvic radiation

• Patients with a history of other malignancies, except: adequately treatednon-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or othersolid tumours curatively treated with no evidence of disease for >= 5 years

• Clinical evidence of distant metastasis as determined by pre-surgical orpost-surgical imaging (CT scan of chest, abdomen and pelvis or whole-body PET-CTscan)

• SUB-STUDY A: Isolated tumour cell(s) identified in lymph node(s) for patients inCohort A1

• SUB-STUDY B: Abnormal p53 and/or mismatch repair deficiency on immunohistochemistrywithout pathogenic POLE mutation.

• Abnormal p53 can also be determined by TP53 mutations found on DNA testing.

• SUB-STUDY B: p53wt/NSMP endometrial carcinoma with a MELF (microcystic, elongatedand fragmented) pattern of myoinvasion and/or substantial lymphovascular invasion

• SUB-STUDY B: Stage IA (not confined to polyp), grade 3, pN0, with substantial LVI.Stage IB, grade 1 or 2, pNx/N0, with substantial LVI

• SUB-STUDY B: Isolated tumour cell(s) identified in lymph node(s)