68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT for the Early and Late Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer Patients: A Prospective Study

Abstract
⁶⁸Ga-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) PET/CT has demonstrated promising clinical results, with a higher SUV_max and tumor-to-background ratio (TBR) in breast cancer (BC) patients than ¹⁸F-FDG PET/CT. Here, we aimed to evaluate the suitability of ⁶⁸Ga-FAPI PET/CT for the early and late prediction of the pathologic response to neoadjuvant chemotherapy (NAC) in BC.

Methods
Twenty-two consecutive patients with newly diagnosed BC and an indication for NAC were prospectively included. All patients underwent standard chemotherapy and ⁶⁸Ga-FAPI PET/CT at baseline, after 2 cycles of NAC (PET2), and 1 wk before surgery (PET3). SUV_max was measured in the primary tumor region and positive regional lymph nodes. The expression of fibroblast activation protein in the primary lesion was analyzed by immunohistochemistry.

Results
Seven patients (31.8%) achieved a pathologic complete response (pCR), and 15 (68.2%) had residual tumors. Thirteen patients (59.1%) showed concentric withdrawal of the primary tumor, and 9 (40.9%) showed diffuse withdrawal. Between PET2 and PET3, the ΔSUV_max of the primary tumor (R ² = 0.822; P = 0.001) and metastatic lymph nodes (R ²= 0.645; P = 0.002) were significantly correlated. The absolute values of SUV_max and TBR at PET2 and PET3 were lower in patients with pCR than in those without pCR (P < 0.05). Moreover, a larger ΔSUV_max at any time point was strongly associated with pCR (P < 0.05). Similar downward trends in SUV_max, TBR, and ΔSUV_max were observed in the pattern of primary tumor reduction. For predicting pCR, the optimal cutoff values for ΔSUV_max after 2 chemotherapy cycles, ΔSUV_maxbefore surgery, TBR after 2 chemotherapy cycles, and TBR before surgery of the primary tumor were 3.4 (area under the curve [AUC], 0.890), 1.1 (AUC, 0.978), -63.8% (AUC, 0.879), -90.8% (AUC, 0.978), 7.6 (AUC, 0.848), and 1.4 (AUC, 0.971), respectively. Immunohistochemistry showed that the SUV_max and TBR of ⁶⁸Ga-FAPI PET/CT were positively correlated with fibroblast activation protein expression (P < 0.001 for both).

Conclusion
Assessment of early changes in ⁶⁸Ga-FAPI uptake during NAC by ⁶⁸Ga-FAPI PET/CT can predict pCR and primary tumor concentric withdrawal in BC patients. ⁶⁸Ga-FAPI PET/CT has great potential for the early and late prediction of the pathologic response to NAC in BC.