Universität zu Köln

Llop-Guevara, A., Loibl, S., Villacampa, G., Vladimirova, V., Schneeweiss, A., Karn, T., Zahm, D. -m., Herencia-Ropero, A., Jank, P., van Mackelenbergh, M., Fasching, P. A., Marme, F., Stickeler, E., Schem, C., Dienstmann, R., Florian, S., Nekljudova, V., Balmana, J., Hahnen, E., Denkert, C. and Serra, V. (2021). Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann. Oncol., 32 (12). S. 1590 - 1597. AMSTERDAM: ELSEVIER. ISSN 1569-8041

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Abstract

Background: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum- based neoadjuvant chemotherapy (NACT). Patients and methods: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet (R)-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and gH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice (R)). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score <= 10% (RAD51-low). Results: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar diseasefree survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Llop-Guevara, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loibl, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Villacampa, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vladimirova, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneeweiss, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Karn, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zahm, D. -m. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herencia-Ropero, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jank, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Mackelenbergh, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fasching, P. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marme, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stickeler, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schem, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dienstmann, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Florian, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nekljudova, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Balmana, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Denkert, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Serra, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-603521
DOI:	10.1016/j.annonc.2021.09.003
Journal or Publication Title:	Ann. Oncol.
Volume:	32
Number:	12
Page Range:	S. 1590 - 1597
Date:	2021
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1569-8041
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PATHOLOGICAL COMPLETE RESPONSE; NEOADJUVANT CHEMOTHERAPY; CARBOPLATIN; MONOTHERAPY Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60352