A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer.
Humans
Pancreatic Neoplasms
/ drug therapy
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
BRCA1 Protein
/ genetics
Gemcitabine
Cicatrix
/ chemically induced
Retrospective Studies
BRCA2 Protein
/ genetics
Fluorouracil
Leucovorin
Deoxycytidine
Paclitaxel
Albumins
Pancreatic Neoplasms
biomarker
genomics
homologous recombination repair
pancreatic neoplasms
platinum
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
03 08 2023
03 08 2023
Historique:
received:
21
01
2023
accepted:
12
05
2023
medline:
7
8
2023
pubmed:
24
6
2023
entrez:
24
6
2023
Statut:
ppublish
Résumé
Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging. Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features. A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(-) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling. A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed.
Sections du résumé
BACKGROUND
Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging.
METHODS
Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features.
RESULTS
A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(-) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling.
CONCLUSION
A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed.
Identifiants
pubmed: 37354528
pii: 7206909
doi: 10.1093/oncolo/oyad178
pmc: PMC10400136
doi:
Substances chimiques
folfirinox
0
BRCA1 protein, human
0
BRCA1 Protein
0
Gemcitabine
0
BRCA2 protein, human
0
BRCA2 Protein
0
Fluorouracil
U3P01618RT
Leucovorin
Q573I9DVLP
Deoxycytidine
0W860991D6
Paclitaxel
P88XT4IS4D
Albumins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
691-698Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200466
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA263622
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press.
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