Page 75 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Initial clinical trials with 89Zr-immuno-PET in oncology
For 55 evaluable patients with HER2-positive metastatic breast cancer, assessment
of 89Zr-trastuzumab uptake resulted in a positive predictive value of 72% and a
negative predictive value of 88% for prediction of clinical outcome. For early
metabolic response assessment with FDG-PET the positive predictive value was
96% and the negative predictive value was 83%. Intrapatient heterogeneity in
tumor uptake was observed in 46% of patients, as illustrated by Figure 3. When
combining 89Zr-trastuzumab-PET with early FDG-PET response after 1 cycle of
T-DM1, a negative predictive value of 100% was obtained for all concordant
patients (with both a negative 89Zr-trastuzumab-PET, as well as absence of response
on early FDG-PET). This strategy of combining HER2-PET with early FDG-PET 4 response monitoring was able to separate patients with a median time to treatment
failure of 2.8 month from patients with a median time to treatment failure of 15 months.
It is not known why 2/16 patients with a negative 89Zr-trastuzumab-PET did show response on treatment with T-DM1. Some possibilities are lack of receptor overexpression, receptor masking, or an induced response despite low HER2 expression due to the extreme potency of T-DM1. Absence of tumor uptake can also be explained by an insufficient tracer dose due to the extent of tumor load or the amount of soluble HER2 in these patients.
These results support that pre-treatment imaging of HER2-targeting is a promising tool to improve the understanding of tumor heterogeneity in metastatic breast cancer and to select patients who are deemed not to benefit from T-DM1. This might avoid toxicity and costs of T-DM1 and improve patient outcome by switching sooner to a more effective therapy (personalized medicine). A plausible explanation for the added value of early FDG-PET is that although target expression of HER2 is a prerequisite for clinical benefit, even with adequate targeting intracellular resistance mechanisms may be responsible for treatment failure. The authors recommend a future randomized trial with cost-effectiveness as secondary endpoint, to test the concept of interrupting T-DM1 treatment after 1 cycle in case of FDG-PET non-responsiveness, which can be expected in 20% of the patients. As such, this trial paved the road towards improved individualization of anti-HER2 therapy.
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