TCGA publishes molecular profile of uterine carcinosarcoma, offers potential
new treatment options
Researchers from The Cancer Genome Atlas, including Van Andel Research Institute’s own Hui Shen, Ph.D., recently published some surprising findings about the molecular complexity of uterine carcinosarcomas. These rare and aggressive cancers often spread quickly and kill approximately two-thirds of women within five years of diagnosis.
Current treatments for uterine carcinosarcomas are aggressive and intrusive, usually including partial or complete surgical removal of the uterus and lymph nodes, followed by aggressive chemotherapy and abdominal radiation. However, no standard treatment exists, and no targeted chemotherapies have been validated to treat this disease.
The TCGA team hopes that results from this study, which were published in Cancer Cell, can help turn the tide against uterine carcinosarcomas. Most notably, they found alterations in the genome, the epigenome, the transcriptome and the proteome, all of which offer good targets for treatment.
Results of the TCGA study reveal several traits of uterine carcinosarcomas. Among some of the key findings are that uterine carcinosarcomas:
- Demonstrate a high degree of epithelial-mesenchymal transition, which helps explain why uterine carcinosarcomas spread quickly and why they are so aggressive
- Have many mutations that could potentially be targeted with existing drugs
- Almost always have mutations in TP53, a gene that is the most commonly mutated gene across all cancer types and is the focus of many drug development programs
- Often harbor errors in genes that regulate the cell cycle
- Uterine carcinosarcoma accounts for fewer than five percent of all uterine cancers
- About 1-in-50,000 women develop uterine carcinosarcoma each year
- Only about 35 percent of patients live longer than five years beyond diagnosis
“Over the course of this study, we discovered potential targets that may respond well to existing chemotherapies and other targets that could be the focus of new drug development,” says Shen. “We hope these results will help improve future clinical trial design and, ultimately, outcomes for women with this disease.”
Specifically, study authors suggest personalized treatments might include use of PARP, EZH2, cell-cycle, and PI3K pathway inhibitors, drugs that block activities in cellular communication channels related to cancer. In addition, the study found patients may benefit from having chemotherapy regimens matched to mutations in their individual tumors.
Among the surprising findings from this study were that most uterine carcinosarcomas might originate as carcinomas—cancers that begin in the layer lining the organs called the epithelium—that evolve into non-epithelial cancer cells. This may help explain both the disease’s relative rarity and its complex molecular landscape, Shen says.
Uterine carcinosarcomas are rare, representing just 4 to 5 percent of uterine cancers, according to the American Cancer Society. They are notoriously difficult to treat, often requiring a process of trial-and-error during chemotherapy selection, and tend to grow wildly afoul of the original uterine cell types (a term called poorly differentiated).
Moreover, uterine carcinosarcomas are lethal. This cancer kills 65 percent of women within five years of diagnosis, and women whose cancers have spread beyond the uterine muscle at the time of diagnosis have particularly poor prognoses. Almost 80 percent of patients will die from the disease once it has spread, according to the TCGA study.
The hope of this study is to arm researchers and drug developers with the information they need to develop new therapies and improve treatment regimens.
The Cancer Genome Atlas is a collaboration between the NIH’s National Cancer Institute and National Human Genome Research Institute and includes hundreds of scientists at leading organizations around the world. Study results are publically available and have contributed to more than a thousand studies of cancer by independent researchers and to the TCGA research network publications.
Shen’s overall research focuses on the epigenome and its interaction with the genome in various diseases, with a specific emphasis on female cancers and cross-cancer comparisons. She is a member of the TCGA Research Network and was co-first author of the study.