FDG SUV demonstrated substantial decline over a 2-week course of AI therapy. This is consistent with the reasoning that if hormone-dependent breast cancers respond to estradiol challenge with an increase in FDG uptake [16–18], then tumors dependent upon the ER pathway for growth should display a decline in FDG uptake as AI therapy lowers estradiol levels. These early declines in FDG uptake corresponded to low post-therapy proliferation (Ki-67), which predicts early response to endocrine therapy . For all 11 patients in the AI group who showed an SUV decline of 20% or greater, the Ki-67 at follow-up was ≤5%; for all three AI patients who did not attain SUV reductions of 20% or greater, the Ki-67 at follow-up was >5%. This supports the feasibility of serial FDG SUV as an early indicator of response to endocrine therapy.
For trastuzumab, 6 of 12 patients showed substantial decreases in FDG PET SUV, including 2 of 3 patients with serial biopsy, but none of the three 2-week biopsies had Ki-67 expression ≤5%. Although numbers are too small to draw conclusions, a less consistent pattern of change is perhaps not surprising. Earlier studies have suggested that T may mediate apoptotic pathways , rather than resulting in an early change in proliferation. In clinical practice and in most studies, T is given in combination with chemotherapy. Data emerging from recent neoadjuvant clinical trials suggest that HER2+ disease can be effectively targeted with additional agents aimed at HER2 such as lapatinib  and pertuzumab . Further study is needed before drawing any conclusions about the efficacy of FDG PET as an early indicator of response to trastuzumab or other HER2-targeted therapies.
We did not see correspondence between change in FDG uptake and change in Ki-67 with AI therapy. Although post-therapy Ki-67 may be a better biomarker than the change in Ki-67 (in the context of predicting breast cancer recurrence) , other possible contributing factors are attributable to the preliminary nature of our pilot study. Of the 17 baseline tissue samples available for pre-post comparisons, 11 were archival (8 AI 3 T), with intervening therapies including cytotoxic chemotherapy, endocrine therapy, and HER2-targeted therapy. Small sample size and heterogeneity of disease characteristics and tissue biopsy sites may also confound our comparisons of imaging parameters to the change in Ki-67.
Another limitation of our study was the timing of imaging and biopsy. Our intentions were to assess the same lesion by imaging and biopsy and to schedule FDG PET scans before biopsy. However, clinical scheduling (diagnostic biopsy preceding PET scans) and feasibility concerns (i.e., imaging of lesions near a high-contrast organ or biopsy of an inaccessible tumor) had to be accommodated. We did not find evidence that post-biopsy inflammation strongly affected SUV. For three AI patients with baseline FDG PET within 21 days after biopsy of the index lesion (6, 13, 17 days), the percent changes in SUV were −28%, −7%, and −3%. For the three AI patients with post-therapy FDG PET within 21 days after biopsy (3, 5, 7 days), the percent changes in SUV were −14%, −47%, and −60%. If post-biopsy SUV were inflated, the opposite trend (greater decrease when the baseline scan occurred post-biopsy, lesser decrease when the post-therapy scan occurred post-biopsy) would be expected. Extension of run-in periods may be considered to avoid having post-therapy scans within a healing period after the baseline biopsy.
Our choice of a 20% threshold as attributable to therapy was motivated by our hypothesis that short-term exposure would produce a pharmacodynamic effect detectable by FDG PET and beyond the limits of agreement in test-retest studies. This is a different task than the estimation of clinical response, for which alternative measures such as PERCIST 1.0 have been suggested. Of note, 8 of the 20 AI group patients with early response by FDG PET SUV had decreases between 20% and 30%, and 4 of those had absolute change in SUV of less than 1.2. Alternative measures of FDG uptake may provide more robust evidence of a drug response ; however, such analysis was beyond the scope of this pilot study.