Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer
Joanne L Blum, A Douglas Laird, Jennifer K Litton, Hope S Rugo, Johannes Ettl, Sara A Hurvitz, Miguel Martin, Henri H Roché, Kyung-Hun Lee, Annabel Goodwin, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Julia F Hopkins, Lee A Albacker, Lida A Mina, Joanne L Blum, A Douglas Laird, Jennifer K Litton, Hope S Rugo, Johannes Ettl, Sara A Hurvitz, Miguel Martin, Henri H Roché, Kyung-Hun Lee, Annabel Goodwin, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Julia F Hopkins, Lee A Albacker, Lida A Mina
Abstract
Purpose: PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood.
Experimental design: Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.
Results: In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy.
Conclusions: Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.
Trial registration: ClinicalTrials.gov NCT01945775.
©2022 The Authors; Published by the American Association for Cancer Research.
Figures
References
- Scully R, Panday A, Elango R, Willis NA. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol 2019;20:698–714.
- Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017;355:1152–8.
- Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008;26:3785–90.
- Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 2011;5:387–93.
- Javle M, Curtin NJ. The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy. Ther Adv Med Oncol 2011;3:257–67.
- Morales J, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, et al. . Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr 2014;24:15–28.
- Murai J, Huang SN, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. . Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012;72:5588–99.
- Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, et al. . Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014;13:433–43.
- Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee K-H, et al. . Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753–63.
- de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. . Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov 2017;7:620–9.
- Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke EM, et al. . A Phase II study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO). Clin Cancer Res 2019;25:2717–24.
- Zandarashvili L, Langelier MF, Velagapudi UK, Hancock MA, Steffen JD, Billur R, et al. . Structural basis for allosteric PARP-1 retention on DNA breaks. Science 2020;368:eaax6367.
- European Medicines Agency . TALZENNA® (talazoparib) summary of product characteristics. November 2020. Available from: .
- U.S. Food and Drug Administration. TALZENNA® (talazoparib) prescribing information. 2021. Available from:.
- Tung NM, Boughey JC, Pierce LJ, Robson ME, Bedrosian I, Dietz JR, et al. . Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology guideline. J Clin Oncol 2020;38:2080–106.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast cancer. Version 5. 2020. Available from: .
- Ooi A, Inokuchi M, Horike SI, Kawashima H, Ishikawa S, Ikeda H, et al. . Amplicons in breast cancers analyzed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Hum Pathol 2019;85:33–43.
- Kneissig M, Bernhard S, Storchova Z. Modelling chromosome structural and copy number changes to understand cancer genomes. Curr Opin Genet Dev 2019;54:25–32.
- Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen WJ, et al. . Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol 2018;2018:PO.17.00286.
- Sun C, Yin J, Fang Y, Chen J, Jeong KJ, Chen X, et al. . BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency. Cancer Cell 2018;33:401–16.
- Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. . Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol 2019;3:PO.18.00283.
- Mondal G, Stevers M, Goode B, Ashworth A, Solomon DA. A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers. Nat Commun 2019;10:1686.
- Sokol ES, Pavlick D, Khiabanian H, Frampton GM, Ross JS, Gregg JP, et al. . Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity. JCO Precis Oncol 2020;4:442–65.
- Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. . Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017;18:75–87.
- Sun JX, He Y, Sanford E, Montesion M, Frampton GM, Vignot S, et al. . A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal. PLoS Comput Biol 2018;14:e1005965.
- Turner NC. Next-generation DNA sequencing (NGS) results for tumors from Phase 2 ABRAZO study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients (pts) with advanced breast cancer (ABC) and germline BRCA1/2 (gBRCA) mutations. In: Proceedings of the European Society for Medical Oncology 2019 Congress; 2019Sept 27–Oct 1; Barcelona, Spain. Lugano, Switzerland: Annals of Oncology; 2019. Abstract nr 2575.
- Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. . Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 2016;534:47–54.
- Maxwell KN, Wubbenhorst B, Wenz BM, De Sloover D, Pluta J, Emery L, et al. . BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat Commun 2017;8:319.
- Polak P, Kim J, Braunstein LZ, Karlic R, Haradhavala NJ, Tiao G, et al. . A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 2017;49:1476–86.
- Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res 2009;69:3625–33.
- Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61–70.
- Mollon L, Aguilar A, Anderson E, Dean J, Davis L, Warholak T, et al. . Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer. Cancer Res 2018;78:1207.
- Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. . Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282–8.
- Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M. Relative contributions of BRCA1 and BRCA2 mutations to "triple-negative" breast cancer in Ashkenazi Women. Breast Cancer Res Treat 2011;129:185–90.
- Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2:a001008.
- Meric-Bernstam F, Zheng X, Shariati M, Damodaran S, Wathoo C, Brusco L, et al. . Survival outcomes by TP53 mutation status in metastatic breast cancer. JCO Precis Oncol 2018;2018:PO.17.00245.
- Hodgson D, Lai Z, Dearden S, Barrett JC, Harrington EA, Timms K, et al. . Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD. Ann Oncol 2021;32:1582–9.
Source: PubMed