89Zr-Trastuzumab PET/CT Imaging of HER2-Positive Breast Cancer for Predicting Pathological Complete Response after Neoadjuvant Systemic Therapy: A Feasibility Study

Abstract

Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (⁸⁹Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation.

Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a ⁸⁹Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed.

Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUV_R on PET/CT-1 and PET/CT-2 (ΔSUV_R) in patients with a pPR and pCR of -48% and -90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was -79% and -94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI.

Conclusions: NAT response evaluation using ⁸⁹Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of ⁸⁹Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer.

Keywords: HER2-targeted PET/CT; breast cancer; human epidermal growth factor receptor 2; neoadjuvant therapy; surgery-free treatment strategy; treatment response evaluation.

Figure 1

Diagnostic MRI- and ⁸⁹Zr-trastuzumab-PET/CT images pre- and post-NAT correlated to histopathology in the resected primary tumor. Shown here are three subjects, two with a pCR and one with a pPR. MRI-1 and PET/CT-1 localized all breast cancer lesions accurately. MRI-2 accurately specified these three patients for complete/partial response. Qualitative assessment of PET/CT-2 accurately identified the two patients with a pCR. As shown in the right panel, qualitative assessment of PET/CT-2 classified the subject with a pPR incorrectly as a pCR, and therefore is a false negative. Of note, the SUV_R% in this patient (−57%) is considerably lower compared to the two patients with a pCR (−91% and −83%). Shown in the lower panels are the hematoxylin and eosin (H&E) staining of the resected specimen, as well as HER2 staining on, respectively, the diagnostic biopsy (Subject 1 and 2) and the resected primary tumor specimen containing residual tumor (Subject 3). * Patient with bilateral lesion; left: invasive carcinoma; right: ductal carcinoma in situ (DCIS). Created with Biorender.com. Abbreviations: H&E, hematoxylin and eosin staining; MRI, magnetic resonance imaging; NAT, neoadjuvant systemic therapy; pCR, pathological complete response; pPR, pathological partial response; SUV_R, standardized uptake value ratio; TBR, tumor-to-blood ratio.

Figure 2

Diagnostic MRI- and ⁸⁹Zr-trastuzumab-PET/CT images pre- and post-NAT correlated to histopathology in the resected sentinel lymph node. Shown here are two subjects, both with a nodal pCR. Pre-NAT MRI and ⁸⁹Zr-trastuzumab-PET/CT localized the tumor positive lymph nodes accurately. Post-NAT MRI accurately specified both patients for complete response. Post-NAT ⁸⁹Zr-trastuzumab-PET/CT accurately specified one of the two patients with a pCR. As shown in the right panel, ⁸⁹Zr-trastuzumab-PET/CT classified one subject with a pCR incorrectly as a pPR, and therefore is classified as False Positive. Created with Biorender.com. Abbreviations: H&E, hematoxylin and eosin staining; MRI, Magnetic Resonance Imaging; NAT, neoadjuvant systemic therapy; pCR, pathological complete response; pPR, pathological partial response; SUV_max, Maximum Standardized Uptake Value.