Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance.
We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples.
Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes.
We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy.
EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
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Clinical data can be accessed through the EORTC data-sharing platform (for details, see www.eortc.org/data-sharing). NGS data can be accessed through the European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/, cram files EGAD00001003334, study accession number EGAS00001001223). The NGS data are only accessible under a Managed Access Agreement (for details, see www.ebi.ac.uk/ega/dacs).
Code is available on request to AC or RI.
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We thank the patients, doctors and nurses involved in the EORTC 10994/BIG 1-00 study for their generous participation. We thank Ultan MacDermott and the Sanger Sample Management and Sequencing team for processing the specimens for NGS.
We thank the Fondation pour la lutte contre le cancer et pour des recherches medico-biologiques, the Site de Recherche Intégrée sur le Cancer—Bordeaux Recherche Intégrée Oncologie Grant INCa-DGOS-Inserm 6046, and the Breast Cancer Working Group EBCC12 grant for financial support. The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the study data and the final responsibility for the decision to submit for publication. Trial design, conduct, and analysis were done at the EORTC headquarters, the Institut Bergonié and Wellcome Sanger Institute independently from all funding bodies.
Ethics approval and consent to participate
The EORTC 10994 clinical trial was registered with ClinicalTrials.gov number NCT00017095 and approved by National and/or Local Ethics Committees in all participating centres. Before registration, all patients signed an informed consent for the trial and for mandatory p53 gene assessment on tumour samples. Patients involved in this substudy gave consent for additional biological research on their tumour samples. The study was performed in accordance with the Declaration of Helsinki.
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The authors declare no competing interests.
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Chatzipli, A., Bonnefoi, H., MacGrogan, G. et al. Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer. Br J Cancer 125, 1356–1364 (2021). https://doi.org/10.1038/s41416-021-01526-3