The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma
Abstract
A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. Significance: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity. This article is highlighted in the In This Issue feature, p. 151
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Cites
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
Mirza, M. R., Monk, B. J., Herrstedt, J., Oza, A. M., Mahner, S., Redondo, A., Fabbro, M., Ledermann, J. A., Lorusso, D., Vergote, I., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1611310 · Cited by 2,451
Self-citationDNA-Repair Defects and Olaparib in Metastatic Prostate Cancer
Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., Nava Rodrigues, D., Robinson, D., Omlin, A., Tunariu, N., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1506859 · Cited by 2,185
Frampton, G. M., Fichtenholtz, A., Otto, G. A., Wang, K., Downing, S. R., He, J., Schnall-Levin, M., White, J., Sanford, E. M., An, P., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2696 · Cited by 2,157 · cited 1×
“Sequencing of formalin-fixed paraffin-embedded tumor specimens was performed using the Foundation Medicine T5 NGS-based assay (29), which sequences the exons of 287 cancer-related genes, including BRCA1, BRCA2, and TP53.”
MethodOlaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer
Ledermann, J., Harter, P., Gourley, C., Friedlander, M., Vergote, I., Rustin, G., Scott, C., Meier, W., Shapira-Frommer, R., Safra, T., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1105535 · Cited by 1,883
Self-citationColeman, R. L., Oza, A. M., Lorusso, D., Aghajanian, C., Oaknin, A., Dean, A., Colombo, N., Weberpals, J. I., Clamp, A., Scambia, G., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32440-6 · Cited by 1,693
Self-citationWhole–genome characterization of chemoresistant ovarian cancer
Patch, A.-M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., Nones, K., Cowin, P., Alsop, K., Bailey, P. J., et al. (2015) · Nature · doi:10.1038/nature14410 · Cited by 1,569
Swisher, E. M., Lin, K. K., Oza, A. M., Scott, C. L., Giordano, H., Sun, J., Konecny, G. E., Coleman, R. L., Tinker, A. V., O'Malley, D. M., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30559-9 · Cited by 1,196
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Cited by
PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance
Rose, M., Burgess, J. T., O’Byrne, K., Richard, D. J., & Bolderson, E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564601 · Cited by 719
PARP and PARG inhibitors in cancer treatment
Slade, D. (2020) · Genes & Development · doi:10.1101/gad.334516.119 · Cited by 667
Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline
Konstantinopoulos, P. A., Norquist, B., Lacchetti, C., Armstrong, D., Grisham, R. N., Goodfellow, P. J., Kohn, E. C., Levine, D. A., Liu, J. F., Lu, K. H., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.02960 · Cited by 381
The forefront of ovarian cancer therapy: update on PARP inhibitors
Mirza, M. R., Coleman, R. L., González-Martín, A., Moore, K. N., Colombo, N., Ray-Coquard, I., & Pignata, S. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.06.004 · Cited by 365
Self-citationOvercoming resistance to tumor-targeted and immune-targeted therapies
Aldea, M., Andre, F., Marabelle, A., Dogan, S., Barlesi, F., & Soria, J.-C. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1638 · Cited by 311
Metadata
- Authors
- Lin, K. K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L.-T., Mann, E., Isaacson, J. D., Maloney, L., O'Malley, D. M., Chambers, S. K., Kaufmann, S. H., Scott, C. L., Konecny, G. E., Coleman, R. L., Sun, J. X., Giordano, H., Brenton, J. D., Harding, T. C., McNeish, I. A., & Swisher, E. M.
- Venue
- Cancer Discovery
- Published
- 2019-02-01
- Volume
- 9
- Issue
- 2
- Pages
- 210-219
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2901506506
- Cited by
- 432
- References
- 29
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. https://app.cochat.ai/papers/10.1158/2159-8290.cd-18-0715
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- Lin, K. K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L.-T., Mann, E., Isaacson, J. D., Maloney, L., O'Malley, D. M., Chambers, S. K., Kaufmann, S. H., Scott, C. L., Konecny, G. E., Coleman, R. L., . . . Swisher, E. M. (2019). BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-18-0715
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