Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CT

Abstract

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies are successful in patients with HER2-positive malignancies; however, spatial and temporal heterogeneity of HER2 expression may prevent identification of optimal patients for these therapies. Purpose To determine whether imaging with the HER2-targeted PET tracer zirconium 89 (⁸⁹Zr)-pertuzumab can depict HER2-positive metastases in women with HER2-negative primary breast cancer. Materials and Methods From January to June 2019, women with biopsy-proven HER2-negative primary breast cancer and biopsy-proven metastatic disease were enrolled in a prospective clinical trial (ClinicalTrials.gov NCT02286843) and underwent ⁸⁹Zr-pertuzumab PET/CT for noninvasive whole-biopsy evaluation of potential HER2-positive metastases. ⁸⁹Zr-pertuzumab-avid foci that were suspicious for HER2-positive metastases were tissue sampled and examined by pathologic analysis to document HER2 status. Results Twenty-four women (mean age, 55 years ± 11 [standard deviation]) with HER2-negative primary breast cancer were enrolled. Six women demonstrated foci at ⁸⁹Zr-pertuzumab PET/CT that were suspicious for HER2-positive disease. Of these six women, three had biopsy-proven HER2-positive metastases, two had pathologic findings that demonstrated HER2-negative disease, and one had a fine-needle aspirate with inconclusive results. Conclusion Human epidermal growth factor receptor 2 (HER2)-targeted imaging with zirconium 89-pertuzumab PET/CT was successful in detecting HER2-positive metastases in women with HER2-negative primary breast cancer. This demonstrates the ability of targeted imaging to identify patients for targeted therapies that might not otherwise be considered. © RSNA, 2020 Online supplemental material is available for this article. See the editorial by Mankoff and Pantel in this issue.

Graphical abstract

Figure 1a:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1b:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1c:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1d:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1e:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1f:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 1g:

Identification of human epidermal growth factor receptor 2 (HER2)-positive metastases in a 66-year-old woman with HER2-negative primary breast cancer by using HER2-targeted zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT. (a) HER2 immunohistochemistry of the primary breast malignancy at 200× magnification was 1+ (faint staining, arrow), consistent with HER2-negative malignancy. (b) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates multiple osseous and hepatic foci, suspicious for HER2-positive malignancy (arrows show hepatic [standardized uptake value, 18.1] and osseous [standardized uptake value, 16.5] reference lesions). (c) Axial CT image in patient in prone position acquired from a CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus. (d) HER2 immunohistochemistry at 200× magnification of the biopsied lesion was 2+ (moderate staining, arrow); 2+ HER2 immunohistochemistry is considered equivocal and thus HER2 fluorescence in situ hybridization (FISH) was performed. (e) HE (CEP17) copy number 3.07, and HER2/CEP17 ratio of 3.0, consistent with HER2-positive disease. Given the new diagnosis of HER2-positive metastases, the woman began treatment with docetaxel, trastuzumab, and pertuzumab. (f) Maximum intensity projection image from fluorodeoxyglucose PET/CT performed before initiation of therapy and (g) after 2 months of therapy demonstrate a substantial partial response (arrows in f and g indicate hepatic [standardized uptake value, 4.5 before therapy, standardized uptake value equal to background after therapy] and osseous [standardized uptake value, 8.4 before therapy, standardized uptake value equal to background after therapy] reference lesions).

Figure 2a:

False-positive findings at zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT in a 47-year-old woman with human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer. HER2 immunohistochemistry of the primary breast malignancy was 1+ (not shown), consistent with HER2-negative malignancy. (a) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates osseous foci in the right pelvis (arrows on osseous lesions; standardized uptake values, 13.8 and 11.9), suspicious for HER2-positive malignancy. (b) Axial CT and fused ⁸⁹Zr-pertuzumab PET/CT images acquired from a PET/CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus (arrow). Pathologic analysis demonstrated HER2 immunohistochemistry 2+ and FISH 1.4 (not shown), consistent with HER2-negative disease.

Figure 2b:

False-positive findings at zirconium 89 (⁸⁹Zr)-pertuzumab PET/CT in a 47-year-old woman with human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer. HER2 immunohistochemistry of the primary breast malignancy was 1+ (not shown), consistent with HER2-negative malignancy. (a) Maximum intensity projection image from research ⁸⁹Zr-pertuzumab PET/CT demonstrates osseous foci in the right pelvis (arrows on osseous lesions; standardized uptake values, 13.8 and 11.9), suspicious for HER2-positive malignancy. (b) Axial CT and fused ⁸⁹Zr-pertuzumab PET/CT images acquired from a PET/CT-guided biopsy of an ⁸⁹Zr-pertuzumab–avid osseous focus (arrow). Pathologic analysis demonstrated HER2 immunohistochemistry 2+ and FISH 1.4 (not shown), consistent with HER2-negative disease.