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Copy number aberration analysis to predict response to neoadjuvant anti-HER2 therapy: results from the NeoALTTO phase III clinical trial

David Venet, Mattia Rediti, Marion Maetens, Debora Fumagalli, David N Brown, Samira Majjaj, Roberto Salgado, Lajos Pusztai, Nadia Harbeck, Sarra El-Abed, Yingbo Wang, Cristina Saura, Henry Gomez, Vladimir Semiglazov, Evandro De Azambuja, Jens Huober, Paolo Nuciforo, Serena Di Cosimo, Martine Piccart-Gebhart, Sherene Loi, Françoise Rothé & Christos Sotiriou

abstract

PURPOSE
The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNAs) in predicting pathological complete response (pCR) and survival outcomes in the NeoALTTO trial.

EXPERIMENTAL DESIGN
The neoadjuvant phase III NeoALTTO trial enrolled 455 HER2-positive early-stage breast cancer patients. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0.

RESULTS
Copy number aberrations estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for amplification. Nevertheless, amplification ceased to be predictive once expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the ER-positive subgroup. 6q23-24 deletion was significantly more frequent in wild-type (WT) compared to mutated tumors, with copy number levels resulting significantly associated with lack of pCR only in the WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number.

CONCLUSIONS
Our analysis identified copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. expression outperformed amplification. The complexity of the 6q23-24 region warrants further investigation.
   
citation Venet D, Rediti M, Maetens M, Fumagalli D, Brown D N, Majjaj S, Salgado R, Pusztai L, Harbeck N, El-Abed S, Wang Y, Saura C, Gomez H, Semiglazov V, de Azambuja E, Huober J, Nuciforo P, Di Cosimo S, Piccart-Gebhart M, Loi S, Rothé F, Sotiriou C. Copy number aberration analysis to predict response to neoadjuvant anti-HER2 therapy: results from the NeoALTTO phase III clinical trial. Clin Cancer Res 2021;.
   
type journal paper/review (English)
date of publishing 28-07-2021
journal title Clin Cancer Res
ISSN electronic 1557-3265
PubMed 34321278
DOI 10.1158/1078-0432.CCR-21-1317