Intrapatient Intermetastatic Heterogeneity Determined by Triple-Tracer PET Imaging in mCRPC Patients and Correlation to Survival: The 3TMPO Cohort Study

Abstract

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both ¹⁸F-FDG and ⁶⁸Ga-prostate-specific membrane antigen (PSMA)-617 PET/CT scans. A third scan with ⁶⁸Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an ¹⁸F-FDG-positive/⁶⁸Ga-PSMA-negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 ¹⁸F-FDG-positive/⁶⁸Ga-PSMA-negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent ⁶⁸Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 ⁶⁸Ga-DOTATATE-positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1-6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine.

Keywords: IIH; PET; intrapatient intermetastatic heterogeneity; metastatic castration-resistant prostate cancer; molecular imaging.

Graphical abstract

FIGURE 1.

3TMPO flow diagram.

FIGURE 2.

(A) Intrapatient intermetastatic phenotypes based on ¹⁸F-FDG (F) and ⁶⁸Ga-PSMA (P) tracer PET/CT in 98 mCRPC patients. (B) Intrapatient intermetastatic imaging phenotypes based on ¹⁸F-FDG (F), ⁶⁸Ga-PSMA (P), and ⁶⁸Ga-DOTATATE (D) PET/CT in 37 mCRPC patients with ≥1 F+/P− lesion who underwent ⁶⁸Ga-DOTATATE scanning. *Phenotypes eligible for PSMA RPT. ^†Phenotypes with IIH. ^‡Phenotypes with ≥1 D+ lesion.

FIGURE 3.

Patient with 5 different lesion phenotypes seen on triple-tracer PET/CT imaging. (A) Coregistered transaxial slices of whole-body maximum-intensity projection PET/CT showing multiple metastases with 3 different radiopharmaceuticals. (B) Discordant expression of 5 representative lesions: bone lesions of seventh left rib (first row) and left scapula (second row), lesions in left iliac (third row) and left supraclavicular (fourth row) lymph nodes, and lesion in right liver lobe (fifth row).

FIGURE 4.

Association of OS with IIH and specific imaging phenotypes. (A) OS of patients with or without IIH. (B) OS of patients with or without ≥1 ¹⁸F-FDG+/⁶⁸Ga-PSMA− lesion. (C) OS among patients who had ≥1 ¹⁸F-FDG+/⁶⁸Ga-PSMA− lesion and underwent ⁶⁸Ga-DOTATATE PET (n = 37) with or without ≥1 ⁶⁸Ga-DOTATATE+ lesion.