A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial
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A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial. / Karn, Thomas; Meissner, Tobias; Weber, Karsten E; Solbach, Christine; Denkert, Carsten; Engels, Knut; Fasching, Peter A; Sinn, Bruno V; Schrader, Iris; Budczies, Jan; Marmé, Frederik; Müller, Volkmar; Holtrich, Uwe; Gerber, Bernd; Schem, Christian; Young, Brandon M; Hanusch, Claus; Stickeler, Elmar; Huober, Jens; van Mackelenbergh, Marion; Leyland-Jones, Brian; Fehm, Tanja; Nekljudova, Valentina; Untch, Michael; Loibl, Sibylle.
In: CLIN CANCER RES, Vol. 26, No. 8, 15.04.2020, p. 1896-1904.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial
AU - Karn, Thomas
AU - Meissner, Tobias
AU - Weber, Karsten E
AU - Solbach, Christine
AU - Denkert, Carsten
AU - Engels, Knut
AU - Fasching, Peter A
AU - Sinn, Bruno V
AU - Schrader, Iris
AU - Budczies, Jan
AU - Marmé, Frederik
AU - Müller, Volkmar
AU - Holtrich, Uwe
AU - Gerber, Bernd
AU - Schem, Christian
AU - Young, Brandon M
AU - Hanusch, Claus
AU - Stickeler, Elmar
AU - Huober, Jens
AU - van Mackelenbergh, Marion
AU - Leyland-Jones, Brian
AU - Fehm, Tanja
AU - Nekljudova, Valentina
AU - Untch, Michael
AU - Loibl, Sibylle
N1 - ©2020 American Association for Cancer Research.
PY - 2020/4/15
Y1 - 2020/4/15
N2 - 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; 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).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.
AB - 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; 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).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.
U2 - 10.1158/1078-0432.CCR-19-1954
DO - 10.1158/1078-0432.CCR-19-1954
M3 - SCORING: Journal article
C2 - 31932495
VL - 26
SP - 1896
EP - 1904
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 8
ER -
