Clinical trial data demonstrate poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitor drug efficacy in individuals with BRCA1/2 pathogenic variants, but not all germline pathogenic variant carriers respond, and some without germline pathogenic variants also derive significant benefit. [18F]FluorThanatrace ([18F]FTT) is a radiolabeled PARP inhibitor that enables noninvasive quantification of PARP-1.1,2 In vitro data demonstrate that the level of PARP-1 correlates positively with cytotoxicity of PARP inhibitors2 and that PARP-1 expression is required for PARP inhibitor efficacy.1-4 In this prospective nonrandomized clinical trial, we report on PARP-1 positron emission tomography imaging using [18F]FTT in patients with breast cancer across a range of breast cancer phenotypes. These proof-of-concept results provide support for testing [18F]FTT as a method for measuring regional PARP-1 expression in breast cancer and as a potential functional biomarker for breast cancer PARP inhibitor response.
This trial (NCT03083288) took place at the University of Pennsylvania from May 2017 to October 2018. The institutional review board at the University of Pennsylvania approved the protocol (Supplement), and written informed consent was obtained from 30 women with untreated stage I through IV breast cancer. Uptake in primary breast tumor was quantified as the partial volume corrected, maximum standardized uptake value (SUV) acquired 50 to 55 minutes postinjection of 351 to 434 MBq (9.5-11.7 mCi) of [18F]FTT. [18F]FTT uptake was compared across breast cancer subtypes segregated by receptor and pathogenic variant carrier status. Germline (n = 29) and tumor (n = 24) DNA were extracted by standard laboratory protocols, or clinical genetic testing was performed (n = 1). DNA repair pathogenic variants were identified, and allele-specific loss of heterozygosity (LOH) was determined as previously described.5 Kruskal-Wallis (nonparametric analysis of variance) or t test was used to determine statistical significance of differences in cancer subtype or BRCA 1/2 pathogenic variant carrier status, respectively (2-sided α = .05), using IBM SPSS Statistics, version 25 (IBM Corp). This study followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guidelines.
[18F]FTT uptake demonstrated a considerable range (maximum SUV, 2.6-11.3 g/mL); tracer uptake was independent of subtype (estrogen receptor–positive, human epidermal growth factor receptor 2–positive, or triple negative) (Table; P = .73). Maximum SUV among BRCA1/2 pathogenic variant carriers was highly variable (range, 2.9-11.3 g/mL), with levels of uptake overlapping the range of BRCA1/2 pathogenic variant noncarriers (Table; P = .50). Anecdotally, higher uptake was noted in tumors of BRCA2 pathogenic variant carriers with allele-specific LOH (patients 21 and 28 were LOH positive; patients 19 and 29 were LOH negative), as might be expected in tumors with functional homologous repair deficiency (Figure). No somatic pathogenic variants in DNA repair genes were identified.
While germline BRCA1/2 pathogenic variant carrier status is currently the accepted biomarker of PARP inhibitor sensitivity, there is variability in response, and overall, more benefit derived by BRCA1 pathogenic variant carriers compared with BRCA2 pathogenic variant carriers. Additionally, multiple ongoing trials examining PARP inhibitor use outside of germline BRCA1/2 indicate a need to find biomarkers for patient selection. Initial results for in vitro biomarkers that include homologous recombination deficiency score, poly–(adenosine diphosphate–ribose) polymers, Rad-51, p53, and microRNAs have been mixed.6 In addition, intratumoral and intertumoral heterogeneity can lead to sampling error, especially in the case of metastatic disease, and pathologic measurements require tissue sampling, which limits the ability for repeat measurements. The study has limitations such as only 30 participants included and the validity of this biomarker to predict response to PARP inhibitors in humans has not been tested, although studies are ongoing and in vitro models have had promising results.1,2
Results of this study demonstrate that in vivo PARP-1 expression is highly variable in breast cancer, and variability appears independent of traditional predictors of increased expression. Although the number of patients is limited, a similar range of [18F]FTT uptake was seen in BRCA pathogenic variant carriers and noncarriers. These early observations support the ability of positron emission tomography to quantitate regional PARP-1 expression. When taken together with preclinical model results,1,2 these findings suggest this approach might help identify patients who will respond to PARP inhibitors. PARP imaging probes might also be used to gain insight into drug pharmacokinetics and pharmacodynamics, including drug delivery. Overall, these early results provide rationale for continued development of [18F]FTT as a companion diagnostic for breast cancer PARP inhibitor therapy.
Accepted for Publication: January 28, 2020.
Corresponding Author: Elizabeth S. McDonald, MD, PhD, Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St, Silverstein Floor 1, Philadelphia, PA 19104-4283 (email@example.com).
Published Online: April 16, 2020. doi:10.1001/jamaoncol.2020.0334
Author Contributions: Drs McDonald and Doot had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: McDonald, Doot, Mach, Maxwell, Mankoff.
Acquisition, analysis, or interpretation of data: McDonald, Doot, Pantel, Farwell, Maxwell.
Drafting of the manuscript: McDonald, Doot, Pantel, Maxwell, Mankoff.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Doot, Maxwell.
Obtained funding: McDonald, Maxwell.
Administrative, technical, or material support: All authors.
Study supervision: McDonald, Pantel, Farwell.
Conflict of Interest Disclosures: Dr Farwell reports receiving grants from Merck and Bristol-Myers Squibb. Dr Mach reports receiving personal fees from Five Eleven Pharma; having a patent pending for a 211At-targeted radiotherapy based on poly–(adenosine diphosphate–ribose) polymerase 1; being a cofounder of and having a US patent license for Trevarx, a company with a license to the patent for the positron emission tomographic imaging agent used in this study; being a cofounder of Accuronix Therapeutics and Vellum Biosciences; and serving on the scientific advisory board of Cognition Therapeutics. Dr Mankoff reports that his spouse is the chief executive officer of Trevarx, a company with a license to the patent for the positron emission tomographic imaging agent used in this study. Dr McDonald reports receiving grants from the National Cancer Institute, Susan G. Komen, METAvivor, the American Roentgen Ray Society, the US Department of Defense, and the National Institutes of Health. No other disclosures are reported.
Funding/Support: Study design, conduct, and data collection were supported by the Abramson Cancer Center Breast Cancer Pilot and Breakthrough Bike Challenge, the National Cancer Institute (P30 CA016520), Basser Center for BRCA, METAvivor, Burroughs Wellcome Fund, and Susan G. Komen (CCR16376362). Support for design and conduct of the study was provided by the National Institutes of Health (K01DA040023, K08CA215312, RO1-CA196528), Susan G. Komen (CCR16376362, SAC130060), the Burroughs Wellcome Fund, and the American Roentgen Ray Society. Support for collection, management, analysis, and interpretation of the data was provided by the National Cancer Institute (P30 CA016520), METAvivor, and the Abramson Cancer Center Breakthrough Bike Challenge.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We would like to thank colleagues at the University of Pennsylvania: Heena Desai, MS, Greg Kelly, MS, and Anh Le, PhD, for help with data collection and analysis; Erin K. Schubert, BS, Theresa E. Berger, MBE, Daniel A. Pryma, MD, and Hsiaoju Lee, PhD, for help with data collection; Anthony J. Young, BS, for help with data analysis; and Amy S. Clark, MD, Payal D. Shah, MD, Susan M. Domchek, MD, and Angela DeMichele, MD for manuscript editing. They were not compensated for their contributions. We also wish to thank the patients in this study for their participation and Meryl Weinreb, MA, a Komen Advocate in Science, for helpful discussions and study review.