American Association for Cancer Research
10780432ccr191954-sup-224024_2_supp_5972296_q2pvy6.pdf (370.13 kB)

Figure S8 from A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial

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journal contribution
posted on 2023-03-31, 22:29 authored by Thomas Karn, Tobias Meissner, Karsten E. Weber, Christine Solbach, Carsten Denkert, Knut Engels, Peter A. Fasching, Bruno V. Sinn, Iris Schrader, Jan Budczies, Frederik Marmé, Volkmar Müller, Uwe Holtrich, Bernd Gerber, Christian Schem, Brandon M. Young, Claus Hanusch, Elmar Stickeler, Jens Huober, Marion van Mackelenbergh, Brian Leyland-Jones, Tanja Fehm, Valentina Nekljudova, Michael Untch, Sibylle Loibl

Hypoxia signature and response by treatment arm


H.W. & J. Hector-Stiftung, Mannheim, Germany



In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were 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%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21–2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00–4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41–2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28–4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature 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.

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