Bevacizumab Reverses Prognosis in Ovarian Cancer Subtypes

Findings from the phase 4 MITO16A/MaNGO OV-2 clinical trial (NCT01706120) show that high immune infiltration, particularly by CD8-positive T cells, is associated with a shorter progression-free survival (PFS) in patients with epithelial ovarian cancer receiving first-line treatment with bevacizumab (Avastin).¹

Gene expression profiling (GEP) analysis was performed on 197 epithelial ovarian cancer samples to classify them into 4 established molecular subtypes: immunoreactive (IMM), differentiated (DIFF), proliferative (PRO), and mesenchymal (MES). The analysis produced an unexpected and pivotal result regarding the prognostic significance of these subtypes in the context of bevacizumab treatment.

The IMM subtype, which is generally associated with the best prognosis in epithelial ovarian cancer, performed significantly worse than expected. In contrast, the MES subtype, typically associated with poor outcomes, had a better prognosis.

The median PFS in the IMM subtype was 25 months, and the median PFS in the MES subtype was 37 months.

“These data suggested that the addition of [bevacizumab] to standard chemotherapeutic treatment differently affects the prognosis of these 2 molecular subtypes, with a detrimental effect for the specific subgroup of patients characterized by a more pronounced immune-related transcriptomic profile,” said Pivetta et al, authors of the study.

The study employed a novel multiplex immunofluorescence (MIF) approach on 292 patient samples. This technique enabled the precise quantification and spatial localization of CD8-positive T cells and CD68-positive macrophages, distinguishing between cells infiltrating the tumor itself (intratumoral) and those in the surrounding connective tissue (stromal).

The analysis confirmed a direct correlation between high levels of immune infiltration and worse patient outcomes. Specifically, a high density of CD8-positive T cells was significantly associated with shorter PFS. When patients were stratified using an optimal cutoff value, high total CD8-positive infiltration was associated with a nearly 2-fold increased risk of disease progression. This association remained statistically significant after adjustment for over-fitting. Infiltration by CD68-positive cells was not found to be significantly associated with either PFS or overall survival (OS). The analysis identified a notable proportion of tumors as immunologically "cold," with 30% of samples being completely negative for CD8-positive cells and 6% negative for CD68-positive cells.

The MIF approach confirmed the negative prognostic value of CD8-positive infiltration.

• Total CD8 infiltration: HR, 1.94 (95% CI, 1.15-3.27; P =.012)
• Tumor CD8 infiltration: HR, 1.83 (95% CI, 1.07-3.12; P=.025)
• Stromal CD8 infiltration: HR, 1.89 (95% CI, 1.11-3.22; P =.018)
• Total CD68 infiltration: HR, 0.94 (95% CI, 0.54-1.62; P = .814)

The combined evidence from GEP and MIF analyses provides a robust foundation for the study's primary conclusion. Both methodologies independently and collectively point to the negative prognostic significance of a preexisting immune infiltrate in patients with epithelial ovarian cancer treated with bevacizumab.

A combined analysis of MIF and GEP data on 171 patients showed that individuals with the worst prognosis tended to have high levels of both CD8-positive and CD68-positive infiltration and belonged to the PRO molecular subtype.

The MITO16A/MaNGO OV-2 trial was a phase 4, multicenter, single-arm study designed to identify clinical and biological prognostic factors for patients with advanced epithelial ovarian cancer.² The standard first-line treatment for these patients includes the antiangiogenic agent bevacizumab combined with carboplatin and paclitaxel chemotherapy. While this regimen has been shown to improve PFS, OS benefits have been inconsistent, and reliable biomarkers to select patients most likely to benefit from bevacizumab are not established.¹ A total of 398 patients were enrolled in the trial. The primary objective was to explore prognostic factors for patients treated with a bevacizumab-containing regimen.

The authors of the study propose that these findings must be validated using samples from randomized clinical trials that directly compare treatment regimens with and without antiangiogenic agents. The authors suggest that further research is needed to understand the biological mechanisms linking VEGFA blockade by bevacizumab with the altered prognostic role of the anti-tumor immune response.

REFERENCES

1.Pivetta E, Canzonieri V, Bagnoli M et al. Tumour-infiltrating leucocytes as prognostic biomarkers in bevacizumab-treated ovarian cancer patients: results from the phase IV MITO16A/MaNGO OV-2 clinical trial. NPJ PrecisOnc. 2025;9(1):355. doi:10.1038/s41698-025-01146-7 

2.Study of clinical and biological prognostic factors in patients with ovarian cancer receiving carboplatin + paclitaxel with bevacizumab (MITO16/MANGO-2). ClinicalTrials.gov. Updated March 24, 2023. Accessed November 20, 2025. https://www.clinicaltrials.gov/study/NCT01706120