@article{814294726bbb49cdb6f438ae2029ec65,
title = "Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer",
abstract = "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.",
keywords = "breast cancer, drug resistance, homologous recombination deficiency, liquid biopsy, PARP inhibitors, platinum",
author = "E. Harvey-Jones and M. Raghunandan and L. Robbez-Masson and L. Magraner-Pardo and T. Alaguthurai and A. Yablonovitch and J. Yen and H. Xiao and R. Brough and J. Frankum and F. Song and J. Yeung and T. Savy and A. Gulati and J. Alexander and H. Kemp and C. Starling and A. Konde and R. Marlow and M. Cheang and P. Proszek and M. Hubank and M. Cai and J. Trendell and R. Lu and R. Liccardo and N. Ravindran and A. Llop-Guevara and O. Rodriguez and J. Balmana and N. Lukashchuk and M. Dorschner and L. Drusbosky and I. Roxanis and V. Serra and S. Haider and Pettitt, {S. J.} and Lord, {C. J.} and Tutt, {A. N.J.}",
note = "Funding Information: This work was funded by Breast Cancer Now through the Breast Cancer Now Toby Robins Research Centre (CTR-Q5-Y3) to ANJT and CJL, a Programme Grant from Cancer Research UK to CJL and ANJT (DRCRPGNov21y100001) and through Breast Cancer Research Foundation (BCRF-23-199) to ANJT. EHJ was supported by a fellowship funded by Cancer Research UK and AstraZeneca. Guardant Health provided plasma ctDNA sequencing. Funding Information: ANJT is/has been a consultant for AstraZeneca, Merck KGaA, Artios, Pfizer, Vertex, GE Healthcare, Inbiomotion, Prime Oncology, Medscape Education, EMPartners, VJ Oncoclogy, Gilead and MD Anderson Cancer Centre; has received grant/research support from AstraZeneca, Myriad, Medivation and Merck KGaA; is a stockholder in Inbiomotion; is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR {\textquoteleft}Rewards to Inventors{\textquoteright} scheme and also reports benefits from this scheme associated with patents for PARP inhibitors paid to ANJT ANJT research accounts at the Institute of Cancer Research. CJL receives and/or has received research funding from AstraZeneca, Merck KGaA and Artios; received consultancy, SAB membership or honoraria payments from Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, Glaxo Smith Kline; has stock in Tango, Ovibio, Hysplex and Tesselate; is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR {\textquoteleft}Rewards to Inventors{\textquoteright} scheme and also reports benefits from this scheme associated with patents for PARP inhibitors paid into CJL{\textquoteright}s personal account and research accounts at the Institute of Cancer Research. AY , JY , MD , and LD are employees and stockholders of Guardant Health. JY is a former full-time employee at Guardant Health and a current full-time employee at Exai Bio. SJP is a named inventor on patents relating to targeting PARPi resistance and stands to gain from their development and use as part of the ICR {\textquoteleft}Rewards to Inventors{\textquoteright} scheme. VS has research grants and receives honoraria from AstraZeneca. ALG and VS are co-inventors of the patent PCT/EP2018/086759 (WO2019122411A1). VS and ALG received funding from Fundaci{\'o} La Marat{\'o} de TV3 (654/C/2019), FERO-GHD and AECC (INVES20095LLOP). NL is employed by AstraZeneca and owns AstraZeneca stock. The other authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
month = apr,
doi = "10.1016/j.annonc.2024.01.003",
language = "English",
volume = "35",
pages = "364--380",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Elsevier",
number = "4",
}
