OBJECTIVE

To perform comprehensive molecular profiling (CGP) on a large cohort of patients with uterine carcinosarcomas to identify potential therapeutic targets.

BACKGROUND

Uterine carcinosarcomas—also known as malignant mixed mesodermal tumors (MMMTs)—comprise only 5% of uterine cancers, yet account for disproportionately more uterine cancer-related deaths owing to their aggressive behavior. Uterine carcinosarcomas present with extrauterine disease in 60% of patients. In patients with early-stage disease (I or II) who receive adjuvant treatment, recurrence rates approach 50%(1).

In advanced stages of disease, the mainstay of treatment remains chemotherapy but cure rates are suboptimal. In a series of 121 patients with uterine carcinosarcomas, five-year stage-specific survival rates were 59, 22, and 9 percent for women with stage I/II, III, or IV disease, respectively(2). Standard treatment options are inadequate, and studies attempting to identify more effective agents have been disappointing.

More research is needed to elucidate the aggressive nature of these cancers, as well as identify treatment targets. More research is needed to elucidate the aggressive nature of these cancers, as well as identify treatment targets.

METHODS

• Tumor samples that underwent CGP by Caris Life Sciences (Phoenix, AZ) with clear indication as uterine MMMT were examined for mutations using NextGen DNA sequencing (NextSeq on 592 genes), protein expression by immunohistochemistry (IHC), copy number amplification using NGS or in situ hybridization (CNA or CISH), and fusion events using NextGen RNA sequencing (FusionPlex on 52 genes).
• Tumor mutational load (TML) was calculated based on the total number of somatic non-synonymous missense mutations identified per megabase of genome coding area. Threshold for TML-high was set at ≥17.
• Microsatellite (MS) instability was evaluated on over 7,000 known MSI loci in target regions. The threshold to determine MSI by NGS was determined to be 46 or more loci with insertions or deletions to generate a sensitivity of > 95% and specificity of > 99%.

CONCLUSIONS

To our knowledge, this is the largest cohort of uterine MMMTs to be molecularly profiled. Multiple somatic mutations and copynumber alterations in genes that are therapeutic targets were identified. Our data suggests CGP may inform treatment, for example, targeting the PI3K/AKT pathway with mTOR inhibition, chromatin remodeling therapies including EZH2 or PARP inhibition, or VEGF inhibition. PD-1/PD-L1 inhibition may be useful in a subset of patients with high TML/MS instability. Clinical trials are needed to validate these observations.