Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer
Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved..
BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance.
PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51.
RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient.
CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:35 |
|---|---|
| Enthalten in: |
Annals of oncology : official journal of the European Society for Medical Oncology - 35(2024), 4 vom: 15. Apr., Seite 364-380 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Harvey-Jones, E [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 15.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.annonc.2024.01.003 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367354195 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367354195 | ||
| 003 | DE-627 | ||
| 005 | 20240416232451.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240121s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.annonc.2024.01.003 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1377.xml |
| 035 | |a (DE-627)NLM367354195 | ||
| 035 | |a (NLM)38244928 | ||
| 035 | |a (PII)S0923-7534(24)00010-3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Harvey-Jones, E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.04.2024 | ||
| 500 | |a Date Revised 15.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance | ||
| 520 | |a PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51 | ||
| 520 | |a RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient | ||
| 520 | |a CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a PARP inhibitors | |
| 650 | 4 | |a breast cancer | |
| 650 | 4 | |a drug resistance | |
| 650 | 4 | |a homologous recombination deficiency | |
| 650 | 4 | |a liquid biopsy | |
| 650 | 4 | |a platinum | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a BRCA1 Protein |2 NLM | |
| 650 | 7 | |a BRCA1 protein, human |2 NLM | |
| 650 | 7 | |a BRCA2 Protein |2 NLM | |
| 650 | 7 | |a BRCA2 protein, human |2 NLM | |
| 650 | 7 | |a PAXIP1 protein, human |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Rif1 protein, human |2 NLM | |
| 650 | 7 | |a TP53BP1 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor p53-Binding Protein 1 |2 NLM | |
| 700 | 1 | |a Raghunandan, M |e verfasserin |4 aut | |
| 700 | 1 | |a Robbez-Masson, L |e verfasserin |4 aut | |
| 700 | 1 | |a Magraner-Pardo, L |e verfasserin |4 aut | |
| 700 | 1 | |a Alaguthurai, T |e verfasserin |4 aut | |
| 700 | 1 | |a Yablonovitch, A |e verfasserin |4 aut | |
| 700 | 1 | |a Yen, J |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, H |e verfasserin |4 aut | |
| 700 | 1 | |a Brough, R |e verfasserin |4 aut | |
| 700 | 1 | |a Frankum, J |e verfasserin |4 aut | |
| 700 | 1 | |a Song, F |e verfasserin |4 aut | |
| 700 | 1 | |a Yeung, J |e verfasserin |4 aut | |
| 700 | 1 | |a Savy, T |e verfasserin |4 aut | |
| 700 | 1 | |a Gulati, A |e verfasserin |4 aut | |
| 700 | 1 | |a Alexander, J |e verfasserin |4 aut | |
| 700 | 1 | |a Kemp, H |e verfasserin |4 aut | |
| 700 | 1 | |a Starling, C |e verfasserin |4 aut | |
| 700 | 1 | |a Konde, A |e verfasserin |4 aut | |
| 700 | 1 | |a Marlow, R |e verfasserin |4 aut | |
| 700 | 1 | |a Cheang, M |e verfasserin |4 aut | |
| 700 | 1 | |a Proszek, P |e verfasserin |4 aut | |
| 700 | 1 | |a Hubank, M |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, M |e verfasserin |4 aut | |
| 700 | 1 | |a Trendell, J |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, R |e verfasserin |4 aut | |
| 700 | 1 | |a Liccardo, R |e verfasserin |4 aut | |
| 700 | 1 | |a Ravindran, N |e verfasserin |4 aut | |
| 700 | 1 | |a Llop-Guevara, A |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez, O |e verfasserin |4 aut | |
| 700 | 1 | |a Balmana, J |e verfasserin |4 aut | |
| 700 | 1 | |a Lukashchuk, N |e verfasserin |4 aut | |
| 700 | 1 | |a Dorschner, M |e verfasserin |4 aut | |
| 700 | 1 | |a Drusbosky, L |e verfasserin |4 aut | |
| 700 | 1 | |a Roxanis, I |e verfasserin |4 aut | |
| 700 | 1 | |a Serra, V |e verfasserin |4 aut | |
| 700 | 1 | |a Haider, S |e verfasserin |4 aut | |
| 700 | 1 | |a Pettitt, S J |e verfasserin |4 aut | |
| 700 | 1 | |a Lord, C J |e verfasserin |4 aut | |
| 700 | 1 | |a Tutt, A N J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Annals of oncology : official journal of the European Society for Medical Oncology |d 1990 |g 35(2024), 4 vom: 15. Apr., Seite 364-380 |w (DE-627)NLM012606308 |x 1569-8041 |7 nnns |
| 773 | 1 | 8 | |g volume:35 |g year:2024 |g number:4 |g day:15 |g month:04 |g pages:364-380 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.annonc.2024.01.003 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 35 |j 2024 |e 4 |b 15 |c 04 |h 364-380 | ||