Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer.
Albumins
Antibodies, Monoclonal
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ drug therapy
Cyclophosphamide
Doxorubicin
Female
Humans
Neoadjuvant Therapy
Paclitaxel
Transforming Growth Factor beta
Triple Negative Breast Neoplasms
/ drug therapy
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:
13 06 2022
13 06 2022
Historique:
received:
06
09
2021
revised:
04
01
2022
accepted:
01
04
2022
pubmed:
5
4
2022
medline:
15
6
2022
entrez:
4
4
2022
Statut:
ppublish
Résumé
We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC). Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial. Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK-STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFβ pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/β-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR. The TGFβ pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.
Identifiants
pubmed: 35377948
pii: 699273
doi: 10.1158/1078-0432.CCR-21-3215
pmc: PMC9464605
mid: NIHMS1797728
doi:
Substances chimiques
130-nm albumin-bound paclitaxel
0
Albumins
0
Antibodies, Monoclonal
0
Biomarkers, Tumor
0
Transforming Growth Factor beta
0
durvalumab
28X28X9OKV
Doxorubicin
80168379AG
Cyclophosphamide
8N3DW7272P
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2587-2597Subventions
Organisme : NCI NIH HHS
ID : R01 CA219647
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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