Changes in Gene Expression Predicting Local Control in Cervical Cancer: Results from Radiation Therapy Oncology Group 0128

Abstract

Purpose:To evaluate the potential of gene expression signatures to predict response to treatment in locally advanced cervical cancer treated with definitive chemotherapy and radiation. Experimental Design: Tissue biopsies were collected from patients participating in Radiation Therapy Oncology Group (RTOG) 0128, a phase II trial evaluating the benefit of celecoxib in addition to cisplatin chemotherapy and radiation for locally advanced cervical cancer. Gene expression profiling was done and signatures of pretreatment, mid-treatment (before the first implant), and ''changed''gene expression patterns between pre-and mid-treatment samples were determined. The ability of the gene signatures to predict local control versus local failure was evaluated. Two-group t test was done to identify the initial gene set separating these end points. Supervised classification methods were used to enrich the gene sets. The results were further validated by leave-one-out and 2-fold cross-validation. Results: Twenty-two patients had suitable material from pretreatment samples for analysis, and 13 paired pre-and mid-treatment samples were obtained. The changed gene expression signatures between the pre-and mid-treatment biopsies predicted response to treatment, separating patients with local failures from those who achieved local control with a seven-gene signature. The in-sample prediction rate, leave-one-out prediction rate, and 2-fold prediction rate are 100% for this seven-gene signature. This signature was enriched for cell cycle genes. Conclusions: Changed gene expression signatures during therapy in cervical cancer can predict outcome as measured by local control. After further validation, such findings could be applied to direct additional therapy for cervical cancer patients treated with chemotherapy and radiation.

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

“…[35][36][37] Additionally, whole transcriptomic RNA-seq analysis was performed, providing a more robust and in-depth characterization of gene expression compared to targeted microarray analysis. Analyzing tumor gene expression before and 3 weeks into CRT provides novel insight into treatment response and offers advantages to analyzing one time point alone.…”

“…36,37 Inclusion in our RNA-seq study mandated the presence of neoplastic cells in cervical tissue 3 weeks into CRT, thus a valid concern is that our study is biased towards tumors that are inherently resistant to treatment. Though we likely could have included more patients had we studied an earlier time point, evaluating gene expression 3 weeks into treatment allows for unique insight into a patient's response to radiation therapy compared to analysis after only a few fractions of radiation, which the existing prior studies have done.…”

Defining the role of TRIP6 in cell physiology and cancer

“…Interestingly, a microarray study identified TRIP6 as one of seven top‐ranked transcripts overexpressed in highly metastatic and therapy‐resistant cervical cancers (Weidhaas et al, 2009). Furthermore, a recent genome‐wide screen identified another hitherto unknown TRIP6 splice variant, which retains its last intron, to be induced in HER2/neu (v‐erb‐b2 erythroblastic leukaemia viral oncogene homologue 2)‐expressing breast cancers, suggesting a possible involvement of TRIP6 in HER2/neu‐mediated tumorigenesis and invasiveness (Ferreira et al, 2010).…”

Radiation Therapy Oncology Group Gynecologic Oncology Working Group

“…27,28 Additionally, using the differential gene expression signatures between the original biopsy and the biopsy at the initial implant, a 7-gene signature panel was identified that could predict outcome in advanced cervical cancer patients from 0128. 29 Immunohistochemistry (IHC) is a powerful technique for measuring protein expression and correlating clinical end points for well-annotated samples in RTOG studies. In 51 patients from RTOG 0116 and 0128, subunit expression of ribonucleotide reductase by IHC was prognostic in nodepositive patients.…”