CDKN2A loss-of-function genetic alterations in uterine sarcoma: prognostic implications and potential therapeutic target

Abstract

<h3>Objectives:</h3> Uterine sarcomas frequently harbor non-actionable oncogenic mutations, limiting the use of targeted therapies. Alterations in the potentially targetable CDK4/6 pathway have recently been described. We explored clinicopathologic differences between uterine sarcomas with CDKN2A loss-of-function genetic alterations and TP53 loss-of-function mutations and sought to determine whether these molecularly defined uterine sarcomas differ in prognosis among early stage patients. <h3>Methods:</h3> Patients with uterine sarcoma were consented to a prospective study of tumor-normal targeted massively parallel sequencing of up to 468 cancer-related genes. Clinicopathologic data were abstracted from the medical record. Fisher's exact tests and Mann-Whitney-U tests were employed to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, compared using log-rank test. <h3>Results:</h3> A total of 229 patients with uterine leiomyosarcoma (LMS; n=191) or undifferentiated uterine sarcoma (UUS; n=38) were identified. The most common genomic alterations were TP53 (62%, n=142) and RB1 (41%, n=94) mutations/homozygous deletions. Furthermore, 10% (n=23) harbored CDKN2A loss-of-function mutations or homozygous deletions, which were mutually exclusive with both TP53 and RB1 alterations (p<0.001). We defined 2 cohorts with uterine-confined sarcoma at diagnosis: 15 with CDKN2A functional loss, and 30 with TP53 alteration but wild-type CDKN2A. The cohorts were clinically and statistically comparable for age at diagnosis, BMI, use of morcellation at initial surgery, tumor size, mitotic rate, presence of LVSI, receipt of adjuvant therapy, and lines of therapy after recurrence. Both cohorts had high rates of hormone receptor positivity (73% vs 83%; p=0.46). The sarcomas harboring CDKN2A loss-of-function genetic alterations demonstrated frequent epithe-lioid/myxoid features and heterologous osteosarcoma elements (53% vs 7%, p=0.001). With median follow-up time of 49.8 months, the median PFS and 4-year OS in the CDKN2A altered sarcomas was 10.3 months (95% CI 2.7-17.8) and 61% vs 17.8 months (95% CI 13.5-22.0) and 87% in the TP53 altered/CDKN2A wild-type sarcomas, p=0.18 for PFS, p=0.12 for OS. <h3>Conclusions:</h3> CDKN2A loss-of-function alterations, found in 10% of uterine sarcomas, are mutually exclusive with TP53 and RB1 alterations commonly present in this malignancy. CDKN2A altered uterine sarcoma may be a genomically and morphologically distinct tumor. We demonstrate poor survival outcomes for patients with early stage disease harboring these CDKN2A alterations. Identifying uterine sarcomas with CDKN2A loss-of-function alterations provides rationale for testing cyclin-dependent kinase inhibitors in this molecular subset.