Research ArticleTheranostics

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Clemens Kratochwil, Frederik L. Giesel, Claus-Peter Heussel, Daniel Kazdal, Volker Endris, Cathleen Nientiedt, Frank Bruchertseifer, Maximilian Kippenberger, Hendrik Rathke, Jonas Leichsenring, Markus Hohenfellner, Alfred Morgenstern, Uwe Haberkorn, Stefan Duensing and Albrecht Stenzinger
Journal of Nuclear Medicine May 2020, 61 (5) 683-688; DOI: https://doi.org/10.2967/jnumed.119.234559

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    (Left) Flowchart of patient selection. Biopsies were taken only from tumor lesions with nonresponse despite high uptake in PSMA PET scans. (Right) Patient with several 18F-FDG–positive (viable) and visually concordant PSMA-positive lesions (green arrows) at baseline. After 3 cycles of PSMA-targeted therapy, residual lesions (18F-FDG–positive) were demasked to be PSMA-negative (red arrows). MIP = maximum-intensity projection.

  • FIGURE 2.
    FIGURE 2.

    (A) In PSMA PET/CT, residual lymph node metastasis with SUV of 37.7 remained after PSMA-targeted α-therapy. (B) In contrast-enhanced CT, location of metastasis was clearly delineated (encircled). (C and D) CT-guided biopsy was performed (C), and histopathologic validation of tumor lesion was obtained, for example, per PSMA immunohistochemistry (D).

  • FIGURE 3.
    FIGURE 3.

    Intrapatient tumor heterogeneity makes tissue sampling of the most appropriate index lesion challenging. (A) Baseline PSMA PET/CT demonstrated group of 3 lymph nodes with homogeneously intense uptake with SUVs of 29.7–35.5 (arrows). (B) After 225Ac-PSMA therapy, 2 lesions with SUVs of 29.7 and 32.0 showed morphologic response (green arrows), but index lesion with highest initial uptake (SUV, 35.5) had increased size (red arrow) and persisting PSMA uptake (SUV, 30.0). (C) This lesion (encircled) was chosen for imaging-guided biopsy.

  • FIGURE 4.
    FIGURE 4.

    (A and B) Baseline PSMA PET demonstrated intense uptake of PSMA ligand in axillary lymph node bulk. (C) Planar emission scan of 225Ac-PSMA validated positive tumor targeting during therapy. (D and E) Restaging PSMA PET revealed morphologic progression and even increased PSMA expression of lesion. (F) Consequently, lesion was chosen for CT-guided biopsy.

Tables

  • TABLE 1

    Patient Characteristics

    Patient no.PSA (ng/mL)Location of metastasesPrevious pharmacotherapyPrevious radiotherapyPrevious radioactive drugs
    1227LN, bone, liver, adrenalAbi, Doce, EnzaRTx, bone177Lu (27.9 GBq)
    2239Bone, LN, lung, skinKeto, Estra, Doce, Abi, Trial, EnzaRTx, local and bone90Y (7.4 GBq)
    3697LN, bone, adrenalAbi, Doce, Trial, CabaziRTx, pelvic and boneNone
    4111LN, boneAbi, Enza, DoceRTx, pelvic and bone177Lu (16 GBq)
    5481LiverAbi, Enza, Doce, CabaziRTx, local and pelvicNone
    6759LN, boneAbi, Enza, Doce, CabaziRTx, local, pelvic, and bone177Lu (44.4 GBq)
    71,658LN, boneAbi, Doce, Cabazi, Estra, EnzaRTx, local and pelvicNone

    • PSA = prostate-specific antigene; LN = lymph node; Abi = abiraterone; Doce = docetaxel; Enza = enzalutamide; RTx = radiotherapy; Keto = ketoconazole; Estra = estramustine; Trial = Phase-1 trial of BAY2010112 (NCT01723475); Cabazi = cabazitaxel.

  • TABLE 2

    Summary of Observed Gene Defects and Previous Exposure to 225Ac-PSMA617

    Patient no.225Ac dose (MBq), cumulativeProbable deleterious mutationWhole-gene deletionLow-level amplificationVariants of unknown significance
    112 (fractions, 6/6)ATMTP53—FAM175A
    214 (fractions, 6/8)BRCA1, PMS1, ×2 TP53——ATM, BARD1, 3xERCC2, ERCC4, FANCB, FANCG
    314 (fractions, 6/8)CHEK2FANCB, NBN, ATMATR, BRIP1 SLX4FANCL, RECQL4
    422 (fractions, 6/6/6/4)———MSH2
    520 (fractions, 8/6/6)PALB2——SLX4
    618 (fractions, 6/6/6)TP53, CHEK2MSH2, MSH6—BRCA1
    718 (fractions, 8/6/4)—BRCA2—ERCC2, SLX4, RAD50
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