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

Thomas Karn, Tobias Meissner, Karsten E Weber, Christine Solbach, Carsten Denkert, Knut Engels, Peter A Fasching, Bruno V Sinn, Iris Schrader, Jan Budczies, Frederik Marme, 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

abstract

PURPOSE
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.

EXPERIMENTAL DESIGN
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.

RESULTS
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; = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; < 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; = 0.006) with a significant interaction with bevacizumab treatment ( = 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 ( = 0.025).

CONCLUSIONS
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.
   
citation Karn T, Meissner T, Weber K E, Solbach C, Denkert C, Engels K, Fasching P A, Sinn B V, Schrader I, Budczies J, Marme F, Müller V, Holtrich U, Gerber B, Schem C, Young B M, Hanusch C, 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.
   
type journal paper/review (English)
date of publishing 13-01-2020
journal title Clin Cancer Res (26/8)
ISSN electronic 1557-3265
pages 1896-1904
PubMed 31932495
DOI 10.1158/1078-0432.CCR-19-1954