Prognostic biomarkers in locally advanced cervical cancer (Cx Ca) treated with chemoradiation (CRT)

Background

Definitive chemoradiation (CRT) is standard therapy for locally advanced cervical cancer (Cx Ca). However, there is a lack of biomarkers to identify patients at increased risk of relapse. Post-therapy ¹⁸F-fluoro-deoxyglucose positron emission tomography (PET) response correlates with outcome, but cannot inform treatment planning. We tested metabolic (glucose transporter [Glut-1]), hypoxic (hypoxia inducible factor [HIF-1a] and carbonic anhydrase [CA-9]) and proliferative (Ki-67) markers for prognostic utility in Cx Ca.

Methods

60 FIGO stage Ib to IVa Cx Ca patients treated with CRT had formalin-fixed paraffin-embedded tumour tissue from pre treatment biopsies. Immunohistochemistry was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore (0-12) by multiplying intensity (0 absent, 1 mild, 2 moderate and 3 intense staining) by a categorical percentage score (0 for none, 1 for 1-24%, 2 for 25-49%, 3 for 50-74% and 4 for ≥75% of cells staining), for each biomarker in each tumour sample. Ki-67 was scored by percentage of positive cells amongst 1000 representative tumour cells. For each biomarker, the cohort was dichotomized and survival estimated by the Kaplan-Meier method and compared using logrank testing.

Results

High Glut-1 expression was associated with inferior progression-free survival (PFS), (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.0 – 7.9, p = 0.049) and overall survival (OS), (HR 5.0, 95% CI 1.3 – 19.2, p = 0.011) on multifactor analysis adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High Glut-1 correlated with increased risk of distant failure (HR 14.6, 95% CI 1.9 - 112.9, p = 0.001) but not with local failure (HR 2.1, 95% CI 0.5 - 8.9, p = 0.48). Low Glut-1 was associated with higher complete metabolic response rate on post-therapy PET scan (odds ratio 3.4, 95% CI 1.0 – 12.3, p = 0.048). Ki-67 was significantly associated with PFS only (HR 1.19 per 10 units increase, 95% CI 1.01 – 1.41, p = 0.033). Biomarkers for hypoxia were not associated with outcome.

Conclusions

High Glut-1 expression in pre-treatment Cx Ca biopsies is associated with worse outcome post CRT. If prospectively validated, Glut-1 may be used to select Cx Ca patients who may benefit from a more intensive treatment regimen.

Clinical trial identification

Legal entity responsible for the study

Division of Medical Oncology, Peter MacCallum Cancer Centre

Funding

Funding for statistical support from the Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

Disclosure

All authors have declared no conflicts of interest.