Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of <i>BRCA2</i> Reversion Mutations Associated with Resistance to PARP Inhibitors

Quigley, David A.; Alumkal, Joshi J.; Wyatt, Alexander W.; Kothari, Vishal; Foye, Adam; Lloyd, Paul; Aggarwal, Rahul; Kim, Won; Lu, Eric; Schwartzman, Jacob; Beja, Kevin; Annala, Matti; Das, Rajdeep; Diolaiti, Morgan E.; Pritchard, Colin C.; Thomas, George V.; Tomlins, Scott A.; Knudsen, Karen E.; Lord, Christopher J.; Ryan, Charles J.; Youngren, Jack; Beer, Tomasz M.; Ashworth, Alan; Small, Eric J.; Feng, Felix Y.

doi:10.1158/2159-8290.cd-17-0146

Cited by 235 publications

(185 citation statements)

References 23 publications

(25 reference statements)

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“…those with high ctDNA fraction). Nevertheless, as liquid biopsies are also showing great promise in monitoring patients for reversion mutations linked to PARPi resistance (27,28), they are likely to have broad clinical utility in patients with HRR defective tumors. Future studies must assess the degree to which defects in other HRR genes (e.g.…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

et al. 2018

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Primary resistance to androgen receptor (AR) directed therapies in metastatic castrationresistant prostate cancer (mCRPC) is poorly understood. We randomized 202 treatment-naive mCRPC patients to abiraterone or enzalutamide, and performed whole exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR directed therapy in mCRPC and identify potential minimally-invasive biomarkers. Statement of SignificanceLeveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely-used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.

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Section: Discussionmentioning

confidence: 99%

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

et al. 2018

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“…BRCA1 and BRCA2 reversion mutations have been documented as potential mechanisms of resistance to platinum-based chemotherapy and PARP inhibitors in cell line models and patient samples (4,13,14,21,46). Here we report on the detection of putative BRCA1 and BRCA2 reversion somatic mutations in the cfDNA of platinum-based chemotherapy and/or PARP inhibitor resistant/ refractory ovarian and breast cancer patients harboring germline BRCA1 or BRCA2 germline mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Although ctDNA frequently comprises only a small fraction of total circulating cell-free (cf)DNA and varies according to disease burden and between cancer types (17), it is possible to detect much of the entire repertoire of somatic genetic alterations found in primary tumors or metastatic disease in cfDNA samples if high-depth sequencing approaches are employed (18–20). In addition, multi-clonal BRCA2 reversion mutations associated with resistance to PARP inhibitors have been identified in cfDNA from two metastatic prostate cancer patients with germline BRCA2 mutations (21). …”

Section: Introductionmentioning

confidence: 99%

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Weigelt

Comino-Méndez

Bruijn

et al. 2017

Clinical Cancer Research

210

129

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Purpose Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of ovarian or breast cancer patients previously treated with platinum and/or PARP inhibitors. Experimental Design cfDNA from 24 prospectively accrued BRCA1- or BRCA2-germline mutant patients, including 19 platinum-resistant/refractory ovarian cancer and five platinum and/or PARP inhibitor pre-treated metastatic breast cancer patients, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function. Results Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four ovarian cancer patients (21%) and from two breast cancer patients (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a breast cancer patient who did not respond to treatment, and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function. Conclusions Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in ovarian and breast cancer patients. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy.

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“…In both high-grade serous ovarian cancer and metastatic prostate cancer, multiple secondary mutations in both germ-line and somatically mutated BRCA2 and PALB2 were identified in cfDNA from patients with recurrent disease (Christie et al 2017, Goodall et al 2017, Quigley et al 2017). Interestingly, in the case of prostate cancers treated with PARPi (either olaparib or talazoparib), analysis of mutations in cfDNA revealed evidence of multiclonal heterogeneity of BRCA2 reversion mutations, information that would be difficult to glean from a single tumor biopsy sample (Quigley et al 2017). In the most extreme case in this study, 34 secondary mutations for BRCA2 c.775_776delAG were identified involving deletions of 1 to 42 bp.…”

Section: Mechanisms Of Resistance To Poly(adp-ribose) Polymerase Imentioning

confidence: 99%

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

Chen

Feng

Lim

et al. 2018

Annu. Rev. Cancer Biol.

256

221

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Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors

Cited by 235 publications

References 23 publications

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

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