Gene Signature Found in Patients With Uterine Serous Carcinoma Who Are Nonresponsive to Treatment

Although uterine cancer is more common in young, Caucasian women who have not had children, there is a rare form of the disease called uterine serous carcinoma (USC) that affects non-Caucasian, postmenopausal women who have had children.¹

Of those patients who do have this rare and aggressive uterine cancer, more than half have a more advanced stage 3 or 4 form of the disease upon diagnosis. These patients, according to researchers, die very quickly.¹

A study recently published in Gynecologic Oncology investigated USC further in order to more quickly identify those patients with an advanced form of the disease and find the appropriate treatment method for them.¹

The results showed that women who do not survive USC have a high expression of a group of 73 genes (USC73). This high USC73 expression resulted not only in a worst prognosis for patients, but also higher cancer cell proliferation and progression rates and lower rates of complete response to standard therapy.¹

These results make clear that a USC73 score is able to act as a biomarker for the identification of women who will not respond to standard treatment. The ability to identify these patients will help researchers conduct efficient clinical trials to find drugs that do work for them, said Jin-Xiong She, PhD, co-author of the study and director of the MCG Center for Biotechnology and Genomic Medicine, Georgia Research Alliance Eminent Scholar in Genomic Medicine, in a press release.²

However, based on these results, researchers are not able to say conclusively that a high USC73 expression is causative of the more aggressive form of USC or just associated with it.¹

“The difference in survival may be caused by something that we are not measuring, making USC73 appear to be correlated to the things we are measuring,” said Lynn Tran, a co-author of the study and MD/PhD student at the Medical College of Georgia at Augusta University, in a press release.²

In order to analyze the USC73 gene signature, the researchers looked at data from 58 patients in the publicly available National Cancer Institute and National Human Genome Research Institute's Cancer Genome Atlas Program (TCGA), which includes matched normal samples, and data from 67 patients at the Georgia Cancer Center. To date, this is one of the largest groups of women with USC ever examined.¹

To analyze gene expression in the patients’ tumors, the researchers focused on RNA, which helped them to more reliably measure the end product protein.¹

A high expression of USC73 was found in 37.9% and 32.8% of the women in the TCGA and Georgia Cancer Center groups, respectively. For some patients, a few of the USC73 genes were at very high levels in the tumors, whereas in others, all of the genes were relatively high.¹

The tumor cells of the patients who had a high USC73 score were found to proliferate more rapidly both in the laboratory dish and in patients, with the cancer cells in the dish proliferating twice as fast as those in patients, She explained in a press release.²

The researchers also found that approximately 90% of patients with low levels of USC73 had a complete response to standard treatment, whereas approximately 50% of patients with high levels had a complete response. Based on these results, the researchers explained in the press release that they suspect there are subtypes within the known subtype of USC that requires a different treatment strategy.²

Although the proliferative nature of the USC73 should work with chemotherapy treatment due to the drug being attracted to rapidly dividing cells, the fact that the carboplatin/paclitaxel regimen does not work in many patients means it may be the wrong chemotherapy, She said. He explained further that the treatment regimen used was adopted from ovarian cancer, despite little evidence it would be effective on uterine cancer.²

Although the researchers still are uncertain regarding the appropriate drugs for treatment of these nonresponsive patients, they think there are better options available than the current standard treatment.¹

For this reason, the researchers have already begun to test the effects of other drugs on the USC73 in a dish and are beginning to look upstream for master regulator transcription factors that control gene expression to see whether at least some can safely be turned off or down, She said.²

Going forward, in order to further assess and understand the clinical utility of the USC73 gene signature, the researchers plan to conduct both a retrospective multicenter study and a prospective clinical trial.²

REFERENCES

• Tran LKH, Tran PMH, Mysona DP, et al. A 73-gene proliferative transcriptomic signature predicts uterine serous carcinoma patient survival and response to primary therapy. Elsevier. 2020. doi: 10.1016/j.ygyno.2020.02.015
• Gene signature found for poor response to standard chemotherapy in rare uterine cancer [news release]. Eurekalert; April 22, 2020. eurekalert.org/pub_releases/2020-04/mcog-gsf042120.php. Accessed April 23, 2020.