September 14 2020
By Carol Aghajanian, MD, NRG Oncology Gynecologic Committee Co-Chair and Chief of Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center
Endometrial cancers are challenging to classify.The staging system is complex and has changed over time.There are multiple histologic types that are difficult to reproducibly diagnose, even by expert gynecologic pathologists.Risk stratification systems; that incorporate age, stage, histologic type, grade and lymph vascular space invasion (LVSI); are designed to predict risk of recurrence, but do not classify tumors by molecular type in a way that would allow appropriate choice of therapy. The Cancer Genome Atlas (TCGA) classified endometrial cancers into 4 groups: POLE, Microsatellite High (MSI-H), Copy Number Low, and Copy Number High.Three classifiers (POLE mutational status, DNA mismatch repair [MMR] immunohistochemistry [IHC] and p53 IHC) replicate the TCGA group assignment, when employed in the order listed.When these 3 classifiers were applied to the PORTEC-3 study (randomized adjuvant chemoradiotherapy [CTRT] versus radiotherapy alone in women with high risk endometrial cancer); recurrence free survival (RFS) was significantly improved with adjuvant CTRT in Copy Number High tumors.No significant benefit was observed from CTRT for patients who classified to the MSI-H group.This exemplifies the need for prospective trials based on molecular classification.
In 2017, the Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.Overall, the rate of MSI-H/dMMR in endometrial cancer is approximately 25% and is predominantly restricted to endometrioid-type cancers.In the recently published Keynote 158 study, that included 49 endometrial cancer patients with recurrent MSI-H/dMMR tumors, the objective response rate to pembrolizumab was 57%.
NRG-GY020 is a phase III randomized trial of radiation therapy +/- pembrolizumab for newly diagnosed early stage high intermediate risk dMMR endometrioid endometrial cancer.The study opened to accrual in February 2020. This trial seeks to prospectively demonstrate whether the addition of PDL1 inhibition to radiation therapy improves 3-year RFS.NRG-GY020 represents the first molecularly selected adjuvant therapy trial in endometrial cancer.
References:
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