Noninvasive Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) in Esophagogastric Cancer Using 89Zr-Trastuzumab PET: A Pilot Study

Abstract

Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). ⁸⁹Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, ¹⁸F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with ¹⁸F-FDG PET. More lesions were identified on ¹⁸F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on ¹⁸F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on ¹⁸F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered (n = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo (n = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion (n = 6) (P = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies.

Keywords: HER2 PET; HER2 heterogeneity; esophageal adenocarcinoma; gastric adenocarcinoma; trastuzumab.

Graphical abstract

FIGURE 1.

Disease sites captured by HER2 and ¹⁸F-FDG PET. (A) ¹⁸F-FDG PET, MRI, and HER2 PET images from a patient with cerebellar metastasis. The images shown are from a patient with de novo metastatic HER2+ GEJ poorly differentiated carcinoma with mixed adeno and squamous differentiation. HER2 PET (right) demonstrated a right cerebellar metastasis (SUV 2.6) without corresponding uptake on ¹⁸F-FDG PET (left) and confirmed on brain MRI (middle). (B) Number of lesions identified by HER2 PET and ¹⁸F-FDG PET among all patients. Total number of lesions avid on HER2 PET (red) and ¹⁸F-FDG PET (blue) is shown. Total numbers of lesions better identified only on HER2 (orange) or ¹⁸F-FDG PET (green) are also shown.

FIGURE 2.

HER2 disease heterogeneity illustrated by ⁸⁹Zr-trastuzumab PET (HER2 PET). (A) ¹⁸F-FDG PET and HER2 PET images from a patient with metastatic HER2+ gastric adenocarcinoma with heterogeneous HER2 expression in the liver. Heterogeneous ⁸⁹Zr-trastuzumab uptake on imaging is shown (blue arrows demonstrate positive lesions, upper figure). Liver biopsy at a site of ⁸⁹Zr-trastuzumab uptake demonstrates HER2 positivity with immunohistochemistry 3+ in 60% of cells (lower). (B) The percentage of tumor load with ⁸⁹Zr-trastuzumab uptake. Patients were stratified into 4 groups by percentage of tumor load showing tracer uptake. Total patients in groups A–D are shown in gray. Number of patients receiving first-line HER2-directed therapy in each group is represented in blue. Patients with at least 1 intense or very intense lesion on HER2 PET (SUV ≥ 10) are represented in red. Of the 15 patients with at least 1 intense or very intense lesion (15/33 [45%]), 6 were in group A (6/33 [18%]) and 7 were in group B (7/33 [21%]). (C) PFS stratified by percentage of tumor load positive in patients receiving first-line HER2-directed therapy (P = 0.353, using permutated log-rank test comparing the 2 groups). (D) PFS stratified by presence of at least 1 lesion with intense or very intense ⁸⁹Zr-trastuzumab uptake (SUV ≥ 10) in patients receiving first-line HER2-directed therapy (P = 0.159, using permutated log-rank test comparing the 2 groups). IHC = immunohistochemistry.

FIGURE 3.

⁸⁹Zr-trastuzumab PET (HER2 PET) and early assessment of response to HER2-directed therapy. (A) ¹⁸F-FDG PET, HER2 PET, and HER2 immunohistochemistry (IHC) in a patient with metastatic HER2+ esophagogastric cancer with a long response to first-line HER2-directed therapy. Patient had > 50% of tumor load with ⁸⁹Zr-trastuzumab uptake on baseline imaging (group B) and at least 1 lesion with SUV ≥ 10. Although primary tumor was avid on baseline HER2 and ¹⁸F-FDG PET, less than 3 wk after initiation of trastuzumab-based treatment, primary tumor remained ¹⁸F-FDG PET avid but was no longer avid on HER2 PET, likely indicating HER2 saturation by trastuzumab. This patient had a PFS of 13 mo on first-line HER2-directed therapy. (B) ¹⁸F-FDG PET and HER2 PET in a patient metastatic HER2+ esophageal adenocarcinoma with a short response to first-line HER2-directed therapy. Patient had > 50% of the tumor load with ⁸⁹Zr-trastuzumab uptake on baseline imaging (group B) but no lesions with SUV ≥ 10; patient had no change in primary tumor ⁸⁹Zr-trastuzumab uptake (SUV 8.1 from 6.6, blue arrows) or in posterior left paraaortic node ⁸⁹Zr-trastuzumab uptake (green arrows) after initiation of first-line HER2-directed treatment. Patient had a relatively short PFS of 6 mo on treatment. 1 L = first-line.