A small hypoxia signature predicts response to neoadjuvant bevacizumab treatment

In breast cancer, adding bevacizumab to neoadjuvant chemotherapy increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. In this prospectively planned study, molecular signatures were tested for prediction of response to neoadjuvant bevacizumab treatment in HER2-negative breast cancer from the neoadjuvant GeparQuinto trial. A total of 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies were profiled using exome-capture RNA-sequencing (RNA-seq) and classified as either of high (N=221) or of low quality (N=68). The high-quality samples were stratified into molecular subtypes by applying the Absolute Intrinsic Molecular Subtypes (AIMS) method as single sample predictor (Paquet and Hallett 2015). A total of 103 (46.6%), 33 (14.9%), 28 (12.7%), 42 (19.0%), and 15 (6.8%) samples were classified as basal-like, HER2-enriched, luminal A, luminal B, and normal-like, respectively. Overall, the pathological complete response (pCR) rate was 49.3% and it was higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) molecular subtypes. T-cell (OR=1.60 [95%CI 1.21-2.12]; p=0.001), proliferation (OR=2.88 [95%CI 2.00-4.15]; p<0.001), and hypoxia (OR=1.92 [95%CI 1.41-2.60]; p<0.001) signatures significantly predicted pCR in univariate analysis. The hypoxia signature remained significant independent predictor of pCR (OR=2.40 [95% CI 1.28–4.51]; p=0.006) in multivariate model and showed a significant interaction with bevacizumab treatment (p=0.020). The hypoxia RNA-signature was validated by immunohistochemistry (IHC) and can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.

Karn T, Meissner T, Weber K, Solbach C, Denkert C, Engels K, Fasching PA, Sinn BV, Schrader I, Budczies J, Marmé F, Müller V, Holtrich U, Gerber B, Schem C, Young B, Hanusch CA, Stickeler E, Huober J, van Mackelenbergh M, Leyland-Jones B, Fehm T, Nekljudova V, Untch M, Loibl S. A small hypoxia signature predicted pCR response to bevacizumab in the neoadjuvant GeparQuinto breast cancer trial. Clin Cancer Res. 2020;26:1896-1904.

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