Table 1 Overview of clinical trials in breast cancer patients aimed at molecular imaging of targets of treatment: HER2, ER, PD-L1 and PARP

HER2

⁸⁹Zr-trastuzumab

14 pts, HER2 + mBC [25]

Dosing of tracer and timing of image acquisition

Relative uptake values in different organs, in tumor lesions and healthy tissue

56 pts HER2 + , mBC [29]

Investigate heterogeneity in HER2 status and evaluate therapy-predictive role for T-DM1

Heterogeneity: 29% had negative PET, 46% heterogeneous uptake

Predictive role: compared to RECIST 1.1, NPV and PPV for HER2-PET were 88% and 72%

Combining HER2- and FDG-PET strongest NPV and PPV (both 100%)

11 pts, HER2- eBC [30]

Investigate whether HER2-PET can identify HER2-positive lesions in previously known HER2-negative tumors

Four patients with uptake on HER2-PET, of which one was confirmed as HER2 + on biopsy. The other 3 were considered as having false-positive HER2-PET results

⁶⁴Cu-DOTA-trastuzumab

8 pts, HER2 + mBC [31]

To detect and measure tumor uptake of trastuzumab

A cold dose of trastuzumab improves image quality

High sensitivity of visualizing HER2 + lesions

18 pts mBC,

2 HER2-PET scans [32]

Compare HER2 status on PET (SUV) and biopsy (ISH)

PET uptake strongly related to pathological HER2 status, but with large interpatient variability

6 pts, HER2 + eBC or mBC [33]

Safety, distribution, internal dosimetry

Feasible for the identification of HER2-positive lesions. Acceptable dosimetry and pharmacologic safety

⁸⁹Zr-pertuzumab

6 pts, HER2 + mBC [26]

First in human

Safety, dosimetry, biodistribution and successful HER2-targeted imaging

24 pts mBC, HER2-neg primary tumor [34]

Evaluate HER2-positive lesions in pts with HER2-neg tumors

6/24 pts with 89Zr-pert avid lesions, of which 3 have biopsy-confirmed HER2 positivity

9 pts, HER2- eBC [26]

Study heterogeneity in HER2 status in patients with HER2-negative primary tumor

5 patients with HER2-uptake on PET; of these, two had biopsy-proven HER2-positive metastases. In the other three, tumor biopsy revealed HER2-negative status, and PET findings were considered false positive

⁶⁸Ga-ABY-025

16 pts, HER2 + mBC [27]

Phase I/II aimed to study the effect of tracer peptide mass, test–retest variability and correlation of quantified uptake with histopathology

Correlation PET-SUV with IHC 0.91, no false-positive tracer uptake in HER2- lesions, SUV 5 times higher in HER2 + vs HER lesions, test–retest intra-class correlation r = 0.996

⁶⁸Ga-DOTA-F(ab’)2-trastuzumab

16 pts mBC, HER2 + and HER2- [35]

First clinical evaluation to study safety, pharmacokinetics, biodistribution and dosimetry profile

Safety was confirmed, no unexpected findings related to dosimetry and distribution. Tumor uptake was seen in 4 out of 8 pts with HER2 + mBC

⁸⁹Zr∙Df-HER2-Fab-PAS200

1 pt, HER2 + mBC [36]

First clinical study

Image acquisition after single dose, lesions could be detected 24 h after injection after appropriate blood clearance

⁶⁸Ga-HER2-Nanobody

20 pts with HER2 + eBC or mBC [37]

Phase 1

Safe. Clear uptake in metastatic lesions, variable uptake in primary breast tumors

⁶⁸Ga-NOTA-MAL-Cvs-

ZHER2:342

2 pts mBC, one HER2 + and one HER2- [38]

Phase 1

SUVmax HER2 + tumors 2.16 ± 0.27), SUVmax HER2- tumors 0.32 ± 0.05

PD-L1

⁸⁹Zr-atezolizumab

4 pts with mTNBC [39]

First In Human study

Tracer uptake in metastatic lesions in all mTNBC patients, no unexpected safety signals

ER

¹⁸F-FES

90 pts with relapsed or de novo metastatic BC [40]

Assess the diagnostic accuracy and safety of 18F-FES-PET/CT to assess ER status

FES-PET positive: 36/36 biopsied with ER + tumor

FES-PET negative: 11/49 biopsied with ER + tumor

SUV_max ¹⁸F-FES vs Allred score r = 0.83, P < 0.0001

19 pts with relapsed BC [41]

Investigate the utility of FES-PET to predict overall response to first-line endocrine therapy and validate previously defined cut-off SUVmean > 1.5

FES SUVmean dynamic vs response to therapy after 6 months: partial response mean SUVmean 2.2 (1.8–3.0); stable disease SUVmean 3.6 (1.9–5.7); progressive disease SUVmean 1.9 (0.2–3.1)

Meta-analysis of 12 trials [42]

Assess lesion-level agreement between ER IHC assays and qualitative assessment by 18F-FES-PET, primary analysis focused on metastatic lesions

Sensitivity metastatic lesions 0.78 (95% CI 0.65–0.88), specificity 0.98 (95% CI 0.65–1)

Prospective trial 200 pts mBC [43]

ER expression in the biopsied metastasis was related to qualitative whole-body ¹⁸F-FES-PET evaluation and quantitative ¹⁸F-FES uptake in the corresponding metastasis

In 200 pts: sensitivity 95% (95% CI 89–97%), specificity 80% (95% CI 66–89%)

¹⁸F-4FMFES

Prospective trial 31 BC pts ER + tumors [44]

Compare diagnostic potential of 18F-4FMFES vs 18F-FES

2.5-fold increase in metabolic stability of ¹⁸F-4FMFES over ¹⁸F-FES. SUV_max similar for both tracers, but improved diagnostic performance related to lower uptake in non-specific tissues for ¹⁸F-4FMFES

PARP

¹⁸F-FTT

Prospective trial in 13 BC pts with PET before and after PARPi treatment [45]

Evaluate in vivo visualization of PARP inhibitor pharmacodynamics, relate blockade of PARP1 expression in vitro or with repeated in vivo imaging

Nine of 13 pts underwent tumor resection and in vitro evaluation of ¹⁸F-FTT uptake with ¹²⁵I-KX1 (an analog of ¹⁸F-FTT and uptake was blocked with PARPi

Of the other 4 patients, 3 had ¹⁸F-FTT PET uptake pretreatment, and all had uptake blocked with treatment with a therapeutic PARPi as seen on a second ¹⁸F-FTT PET

30 pts with untreated stage I-IV BC [46]

Evaluate PARP1 expression in relation to tumor subtype and BRCA mutation status

Overlapping ranges of SUV_max between different tumor subtypes and between patients with and without germline BRCA mutations