Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727).
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 09 2023
15 09 2023
Historique:
received:
08
02
2023
revised:
23
05
2023
accepted:
24
07
2023
medline:
18
9
2023
pubmed:
14
8
2023
entrez:
13
8
2023
Statut:
ppublish
Résumé
The TNT trial (NCT00532727) showed no evidence of carboplatin superiority over docetaxel in metastatic triple-negative breast cancer (mTNBC), but carboplatin benefit was observed in the germline BRCA1/2 mutation subgroup. Broader response-predictive biomarkers are needed. We explored the predictive ability of DNA damage response (DDR) and immune markers. Tumor-infiltrating lymphocytes were evaluated for 222 of 376 patients. Primary tumors (PT) from 186 TNT participants (13 matched recurrences) were profiled using total RNA sequencing. Four transcriptional DDR-related and 25 immune-related signatures were evaluated. We assessed their association with objective response rate (ORR) and progression-free survival (PFS). Conditional inference forest clustering was applied to integrate multimodal data. The biology of subgroups was characterized by 693 gene expression modules and other markers. Transcriptional DDR-related biomarkers were not predictive of ORR to either treatment overall. Changes from PT to recurrence were demonstrated; in chemotherapy-naïve patients, transcriptional DDR markers separated carboplatin responders from nonresponders (P values = 0.017; 0.046). High immune infiltration was associated with docetaxel ORR (interaction P values < 0.05). Six subgroups were identified; the immune-enriched cluster had preferential docetaxel response [62.5% (D) vs. 29.4% (C); P = 0.016]. The immune-depleted cluster had preferential carboplatin response [8.0% (D) vs. 40.0% (C); P = 0.011]. DDR-related subgroups were too small to assess ORR. High immune features predict docetaxel response, and high DDR signature scores predict carboplatin response in treatment-naïve mTNBC. Integrating multimodal DDR and immune-related markers identifies subgroups with differential treatment sensitivity. Treatment options for patients with immune-low and DDR-proficient tumors remains an outstanding need. Caution is needed using PT-derived transcriptional signatures to direct treatment in mTNBC, particularly DDR-related markers following prior chemotherapy.
Identifiants
pubmed: 37574209
pii: 728413
doi: 10.1158/1078-0432.CCR-23-0370
pmc: PMC10502473
doi:
Substances chimiques
Carboplatin
BG3F62OND5
BRCA1 protein, human
0
BRCA1 Protein
0
Docetaxel
15H5577CQD
BRCA2 protein, human
0
BRCA2 Protein
0
Biomarkers
0
Banques de données
ClinicalTrials.gov
['NCT00532727']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3691-3705Subventions
Organisme : Cancer Research UK
ID : A15955
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA058223
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233333
Pays : United States
Organisme : Cancer Research UK
ID : CRUK/07/012
Pays : United Kingdom
Organisme : Cancer Research UK
ID : CTRQQR-2021/100004
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1491–A15955
Pays : United Kingdom
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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