Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer.
Antineoplastic Agents
/ therapeutic use
Breast Neoplasms
/ drug therapy
Female
Gene Amplification
Gene Frequency
/ drug effects
Gene Regulatory Networks
/ drug effects
Humans
Mutation
Neoadjuvant Therapy
Neoplasm, Residual
Receptor, ErbB-2
/ metabolism
Receptors, Estrogen
/ metabolism
Sequence Analysis, DNA
Treatment Outcome
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
25
11
2020
accepted:
11
08
2021
revised:
04
07
2021
pubmed:
5
9
2021
medline:
17
12
2021
entrez:
4
9
2021
Statut:
ppublish
Résumé
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. CLINICALTRIALS.GOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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. CLINICALTRIALS.GOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
Identifiants
pubmed: 34480095
doi: 10.1038/s41416-021-01526-3
pii: 10.1038/s41416-021-01526-3
pmc: PMC8575785
doi:
Substances chimiques
Antineoplastic Agents
0
Receptors, Estrogen
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Banques de données
ClinicalTrials.gov
['NCT00017095']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1356-1364Investigateurs
Sophie Abadie-Lacourtoisie
(S)
Alexandre Bodmer
(A)
Etienne Brain
(E)
Tanja Cufer
(T)
Mario Campone
(M)
Elisabeth Luporsi
(E)
Cristian Moldovan
(C)
Thierry Petit
(T)
Martine Piccart
(M)
Franck Priou
(F)
Elsbieta Senkus
(E)
Khalil Zaman
(K)
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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