Genomic Landscape of ctDNA and Real-World Outcomes in Advanced Endometrial Cancer

Abstract

Purpose: ctDNA is a novel technique extensively studied in solid tumors, although not currently well defined in endometrial cancer.

Experimental design: A de-identified retrospective analysis of 1,988 patients with advanced/recurrent endometrial cancer was performed. In addition, an analysis of a real-world evidence cohort was completed (n = 1,266). Patients underwent ctDNA testing using Guardant360 during routine clinical care. The objective was to describe and assess molecular landscape using ctDNA.

Results: Among 1,988 ctDNA samples, at least one somatic alteration was detected in 91.6% (n = 1,821). Most frequently altered genes were TP53 (64%), PIK3CA (29%), PTEN (25%), ARID1A (20%), and KRAS (14%). Overall, 18.5% had amplifications, with the majority identified in CCNE1 (40.9%), PIK3CA (22%), and EGFR (19.3%). From the real-world evidence cohort, those with TP53 mutations had a worse overall survival (OS) versus those without TP53 mutations (P = 0.02) and those with TP53 comutations had an inferior OS in comparison with TP53-mutated only (P = 0.016). Amongst these, patients with a PIK3CA comutation (P = 0.012) and CCNE1 amplification (P = 0.01) had an inferior OS compared with those with only TP53 mutations. Fifty-seven patients with newly diagnosed endometrial cancer had at least two serial ctDNA samples showing evolution in detected variants compared with baseline samples, with TP53 being the most frequent change.

Conclusions: This study is one of the largest cohorts of ctDNA currently reported in endometrial cancer. The presence of TP53 mutation and other comutations detected by ctDNA have a negative effect on outcomes. This report suggests that ctDNA analysis is feasible and could become a useful biomarker for endometrial cancer.

Figure 1.

Endometrial cancer ctDNA genomic landscape. A, Most common genomic alterations identified in the overall cohort of patients with endometrial cancer. B, Most common genomic alterations identified in patients with endometrial cancer without MSI-H. Variants of uncertain significance were excluded.

Figure 2.

Frequency of genomic alterations. A, In patients with advanced and recurrent endometrial cancer. The most commonly altered genes identified were TP53, PIK3CA, PTEN, ARID1A, and KRAS. Variants of uncertain significance were excluded. B, In newly diagnosed and recurrent endometrial cancer patient samples, alterations in TP53 were more frequently identified in recurrent samples (P < 0.001). C, Incidental pathogenic germline alterations. Sixty-two incidental germline alterations were identified in 61 patient samples, most commonly in BRCA1, BRCA2, and ATM. D, Frequency of gene amplifications in endometrial cancer patient samples. Amplifications were identified in 18.5% (337/1,821), with the majority identified in CCNE1, PIK3CA, EGFR, and ESR1.

Figure 3.

Coalterations with TP53 mutations. A, Coalterations with other types of mutations. Variants of uncertain significance, fusions, and CNVs were excluded. Comutations in FBXW7, PIK3CA, and CHEK2 were frequently identified in the TP53-mutated cohort; meanwhile, comutations in CTNNB1, PTEN, ARID1A, and KRAS were more frequently in those without TP53 mutation. B, Coamplifications with TP53 mutations. CCNE1 amplifications were significantly enriched with TP53 mutations, and EGFR and RAF1 were significantly enriched in those without TP53 mutations.

Figure 4.

Kaplan–Meier curves representing OS. A,TP53-mutated vs. TP53 nonmutated, (B) TP53 comutated vs. TP53-only patients, (C) TP53-PIK3CA vs. TP53-only patients, and (D) CCNE1-amplified vs. CCNE1 nonamplified. Amp, amplified; Comut, comutated; mut, mutated; WT, wild-type.