USC73 Score Predictive of OS in Uterine Serous Carcinoma

Jin-Xiong She, MD

A 73-gene proliferative transcriptomic signature was found to better predict overall survival (OS) outcomes and potentially be used to personalize treatment in patients with uterine serous carcinoma, according to results of a retrospective study.¹

In an analysis of The Cancer Genome Atlas (TCGA) RNAseq data, and by utilizing an elastic net model with all 73 aforementioned genes, investigators were able to distinguish between patients with good and poor OS outcomes.

Patients determined to have good outcomes, and a low USC73 score, demonstrated a 5-year OS rate of 83.3% and a median survival time beyond 5 years. Meanwhile, the poor OS cohort had a 5-year OS rate of 13.3% and a median survival time of 1.67 years with a high USC73 score (HR, 40.1; P = 3 × 10^-8). This finding from the poor OS group was validated in the independent Augusta University cohort (HR, 4.3; P = .0004).

Patients with a high USC73 score from the TCGA and Augusta University cohorts, respectively, comprised 37.9% and 32.8% of the population.² Patients with early-stage disease and a low USC73 score had the best prognosis with the 5-year OS rate of 85.1%. However, patients who had advanced-stage disease with a high USC73 score had the worst prognosis, with a 5-year OS rate of 6.4% (HR, 30.5; P = 1.2 × 10^-12).

“If you can identify the patients who won’t do well and have a very bad prognosis, you can test new drugs on this subset of patients,” said co-investigator, Jin-Xiong She, PhD, professor and director of the Center for Biotechnology and Genomic Medicine with Augusta University, in a press release. “You are going to be able to figure out whether the drug(s) work or not with a much smaller sample size.”²

The initial USC73 score was a median of 8.68, (range, 7.3-10.3) and was used to separate patients into 2 groups: USC73-high and USC73-low patients. RNAseq data for 58 patients were collected from the TCGA USC cohort and the expression of 73 candidate genes was measured for 67 Augusta University samples using NanoString technology. Patients on the study were diagnosed with uterine serous carcinoma between 1999 and 2017, were at least 18 years old, and had sufficient formalin-fixed paraffin embedded (FFPE) tissues (n = 67). The median follow-up time was 2.97 years.

Forty of the 73 genes individually analyzed within the Augusta University validation cohort showed statistically significant survival differences on a Cox proportional hazard analysis. Trending significance in 12 additional genes in regard to survival differences.

TCGA USC73-high patients were commonly identified as being advanced stage and were treated with radiation, as opposed to chemotherapy, while Augusta University USC73-high patients were also advanced stage, they were treated with chemotherapy instead of radiation (P = 3.4 × 10-3; 1.0 × 10-3; and 1.1 × 10-2, respectively).

The USC73 score within the AU validation cohort was a median of 10.1 (range, 7.2-12.4). Similarly, the TCGA cohort saw a 5-year survival rate of 22.7% in the USC73-high group and 70.4% in the USC73-low group, respectively (HR, 4.3; P =.00036). The Augusta University validation cohort saw a median survival time of more than 5 years for the USC73-low patients and 1.91 years for the USC73-high patients.

Univariable Cox proportional hazard analysis for each covariate showed that advanced-stage disease and radiation therapy were indicative of poor prognosis in the TCGA cohort (HR, 7.8 and 5.4; P = 9.1 × 10-4and 3.0 × 10-3, respectively). Advanced-stage disease was also associated with poor prognosis in the Augusta University cohort (HR, 5.4; P = 4.9 × 10-5). A multivariate analysis showed that USC73 affected survival independent of both stage and treatment in TCGA (HR, 27.0, P =.003), and USC73 independent of stage alone in the Augusta University cohort (HR, 3.4; P = .003).

In patients with USC73-high and advanced-stage disease, the 5-year OS rate was 0%. Patients with early stage disease in USC73-high cohort were found to have an intermediate prognosis with a 5-year OS rate of 75% (HR, 9.0).

In the Augusta University validation cohort, advanced-stage was associated with worse prognosis in both USC73-high and USC73-low groups (P = 2.8 × 10-6). The 5-year OS rate was 82.7% in the early-stage USC73-low group, while patients with USC73-high and advanced-stage disease had a 5-year OS rate of 11.6% (HR, 18.4). The advanced-stage USC73-low group and early-stage USC73-high group have intermediate prognosis with a 5-year OS rate of 48.9% and 45%, respectively (HR = 6.5 and 5.5, respectively).

“As a therapeutic biomarker, USC73 may be useful for patient care and future clinical trials. Immediately, USC73 score can tell patients and their physicians about their expected OS if they are treated with the standard therapies, which would have excellent outcome for those early-stage patients with a low USC73 score,” the authors concluded in the study. “However, early-stage patients with high USC73 score, advanced stage patients, and, especially, those advanced stage patients with high USC73 score have bad prognosis and alternative treatment options should be considered. Options may include changing standard chemotherapy combinations to other combinations in the upfront setting, instead of changing upon disease progression.”

References

1. 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. [Published online February 8, 2020]. Gyn Oncol. doi: 10.1016/j.ygyno.2020.02.015

2. Gene signature found for poor response to standard chemotherapy in rare uterine cancer. [News release]. Medical College of Georgia at Augusta University. Published April 22, 2020. Accessed April 28, 2020. https://bit.ly/2W6erFU.