PET Molecular Imaging as a Tool for Precision Oncology

HomeRadiologyVol. 296, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialPET Molecular Imaging as a Tool for Precision OncologyDavid A. Mankoff , Austin PantelDavid A. Mankoff , Austin PantelAuthor AffiliationsFrom the Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St, 1 Donner Building, Philadelphia, PA 19104-4283.Address correspondence to D.A.M. (e-mail: [email protected]).David A. Mankoff Austin PantelPublished Online:Jun 9 2020https://doi.org/10.1148/radiol.2020201969MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See the article by Ulaner et al in this issue.Dr David A. Mankoff is Gerd Muehllehner professor and vice-chair for research in the University of Pennsylvania (Pa) Department of Radiology. His research focuses on translational molecular cancer imaging, especially breast cancer, and quantitative imaging methods.Download as PowerPointOpen in Image Viewer Dr Austin Pantel is an assistant professor of radiology at the University of Pennsylvania. His research focuses on kinetic analysis and human translation of novel radiotracers.Download as PowerPointOpen in Image Viewer Precision oncology, namely the use of cancer biomarkers to guide individualized targeted cancer therapy, has some of its earliest roots in the treatment of breast cancer (1), starting with the use of steroid hormone receptor expression to guide systemic endocrine therapy. For nearly 40 years, routine assay of breast cancer tissue for the expression of steroid receptors (estrogen receptors [ERs] and progesterone receptors) has guided systemic endocrine therapy. ER and progesterone receptor expression drives choices for the adjuvant therapy of early stage breast cancer and primary systemic therapy of metastatic breast cancer. In the metastatic setting, however, receptor expression heterogeneity introduces sampling errors where the assay of receptor expression at one site of disease may not represent expression at all sites. Therapeutic target heterogeneity, both spatial and temporal, has been recognized as an important barrier to effective precision oncology for metastatic cancer, creating a call for methods that might better measure expression for all sites of metastatic disease in a patient (2). PET molecular imaging can quantify regional in vivo cancer biology and depict the full burden of metastatic disease and has generated considerable interest as a tool to guide precision oncology for metastatic breast and other cancers (3). For example, PET imaging of ER expression by using the labeled estrogen, fluorine 18 (18F) fluoroestradiol, has shown the ability to capture the heterogeneity of ER expression in metastatic breast cancer (4) and to help guide endocrine therapy selection (3). Is PET molecular imaging the tool that oncologists have been looking for?Beyond steroid receptors, the discovery of the importance of the human epidermal growth factor receptor 2 (HER2, also known as HER-2/neu and cerbB2) and the development of the HER2-targeted therapeutic agent trastuzumab (5) were major breakthroughs in breast cancer research. These advances have transformed the practice of breast cancer treatment to the great benefit of patients with HER2-expressing breast cancers. Assay of breast cancer tissue for HER2 is now a routine part of practice for both primary and metastatic breast cancer, and patients with biopsy-proven overexpression are administered HER2-targeted agents in both adjuvant and metastatic settings (6). The armamentarium of HER2-targeted drugs has expanded well beyond trastuzumab, and HER2-targeted agents continue to be developed and approved. The recognition that HER2 functions as a heterodimer with other members of the human epidermal growth factor receptor family, especially human epidermal growth receptor 3 (HER3), led to the development of drugs targeting HER2/HER3 heterodimers, including pertuzumab, which is now widely used as part of therapeutic regimens targeting HER2-overexpressing breast cancers (6). Spurred by this development, investigators at Memorial Sloan-Kettering Cancer Center successfully tested a PET agent for imaging HER2-expressing breast cancer, zirconium 89 (89Zr)–pertuzumab (7). This PET imaging probe is the subject of the prospective study of HER2 expression heterogeneity in metastatic breast cancer by Ulaner et al in this issue of Radiology (8).In their innovative study, Ulaner et al tested the ability of 89Zr-pertuzumab PET/CT in identifying HER2-overexpressing metastases arising from non-HER2 overexpressing primary breast cancers. Gain of drug-target expression during metastasis, a phenomenon more common for HER2 than other targets such as ERs and/or progesterone receptors, may make such patients amenable to HER2-targeted therapy (6). Twenty-four patients with documented metastatic breast cancer and five or more metastatic lesions were imaged with 89Zr-pertuzumab PET/CT. For the six patients with one or more sites of 89Zr-pertuzumab–positive disease, PET/CT was used to guide metastatic biopsy. Tissue samples were assayed for HER2 overexpression, which was defined per accepted criteria as either an immunohistochemistry score of 3+ (high-level staining) or an immunohistochemistry score of 2+ with a positive fluorescent in situ hybridization test (6). Of these six patients with 89Zr-pertuzumab–positive disease at PET/CT, three had biopsy-proven HER2 overexpression and two had HER2-negative disease. In one patient, the sample was not satisfactory for HER2 assay. One of the patients with biopsy-proven HER2-overexpressing cancer, a patient who progressed with standard treatment for her original ER-positive HER2-negative breast cancer, showed a substantial partial response to a treatment regimen that included trastuzumab and pertuzumab. Ulaner et al concluded that HER2-targeted imaging with 89Zr-pertuzumab PET/CT may depict HER2-positive metastases in women with HER2-negative primary breast cancer, directing patients to HER2-targeted therapy that otherwise would not have been considered.This important study demonstrates the ability of 89Zr-pertuzumab PET/CT to guide selective biopsy in metastatic breast cancer and to identify a treatment-relevant change in target expression. In addition to directing patients away from therapy where the disease has lost expression of the therapeutic target, as is the case for ER PET (4), this HER2 PET study demonstrated that PET can also direct patients with breast cancer toward new treatments for tumors that have gained target expression. This is exactly the principle of precision oncology—to use biomarkers of the presence or absence of treatment target expression to guide individualized drug selection.Some limitations of the study should be noted, including a small number of patients (n = 24) who were highly selected from a larger pool of eligible patients (n = 65). This creates the potential for selection bias. Because only patients with 89Zr-pertuzumab–positive lesions underwent biopsy, the authors could not estimate the sensitivity of 89Zr-pertuzumab for HER2-overexpressing metastatic breast cancer in this patient population. 89Zr-pertuzumab targets the HER2/HER3 heterodimer and might conceivably help to detect a smaller fraction of HER2-expressing tumors than an agent directed toward HER2 only, such as 89Zr-trastuzumab, which has also been shown to detect HER2 over-expressing breast tumors (9). In the small number of study patients with 89Zr-pertuzumab–positive lesions (n = 6), there were at least two false-positive findings by standard pathologic criteria for HER2 overexpression. It should be noted, however, that tumors with lower levels of HER2 expression that are below the established threshold for determining HER2 overexpression by immunohistochemistry or fluorescent in situ hybridization might be detected at PET and could still benefit from HER2-targeted therapy (6). Nevertheless, this study provides an important proof of principle for the use of PET to help identify patients who may benefit from HER2-targeted therapy. These encouraging results motivate future studies with more extensive tissue sampling and measurement of clinical response to HER2-targeted therapy as an important reference standard for the predictive accuracy of the PET findings.Future studies with 89Zr-pertuzumab might benefit from strategies that have been helpful in other studies that tested PET as an imaging biomarker for targeted therapy. A paired 18F-fluorodeoxyglucose (FDG) PET/CT scan can serve as a sensitive marker of metabolically active breast cancer to help in determining the presence, and specifically the absence, of the therapeutic target by the biomarker PET. Pairing of FDG with a receptor-targeted agent was successfully used in ER PET studies of tumor heterogeneity (4). Serial FDG PET/CT can also be used to determine the effectiveness of treatment, improving the overall predictive value for guiding therapy (3). This was the case for HER2 Imaging Study to Identify HER2 Positive Metastatic Breast Cancer Patient Unlikely to Benefit From T-DM1 (ZEPHIR) study (10), in which a combination of before-therapy HER2 PET and serial FDG PET showed high positive and negative predictive values for HER2-targeted therapy. This strategy can be broadened from studies of PET imaging as integrated (observational) biomarkers in prospective trials of targeted therapy used to assess predictive value and define quantitative thresholds to subsequent trials by using imaging measures as integral (actionable) biomarkers to select therapy. This could pave the way for imaging tests as companion diagnostics for targeted therapy of metastatic breast cancer in the clinical setting (3).Mounting evidence supports the ability of PET molecular imaging to help guide precision oncology, especially in metastatic cancer. The innovative study by Ulaner et al (8) adds to this body of evidence by showing that PET can identify patients whose tumors have gained therapeutic targets that were not present at an earlier stage of disease. Ultimately, PET imaging can lead patients to more effective treatments that would not have been selected based on purely tissue-based biomarker strategies, directing more precise targeting of treatment to tumor biology. Therefore, PET should have a significant role in directing precision oncology, especially in metastatic cancers.Disclosures of Conflicts of Interest: D.A.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed money paid to author for board memberships from ImaginAb and Reflexion; disclosed money paid to author for consultancy from Philips; disclosed relationship with Trevarx; disclosed that wife is CEO of company that works with PET biomarkers not related to the study or editorial. Other relationships: disclosed no relevant relationships. A.P. disclosed no relevant relationships.References1. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA 2019;321(3):288–300. Crossref, Medline, Google Scholar2. Sonnenblick A, Pondé N, Piccart M. Metastatic breast cancer: The Odyssey of personalization. Mol Oncol 2016;10(8):1147–1159. Crossref, Medline, Google Scholar3. Mankoff DA, Farwell MD, Clark AS, Pryma DA. Making Molecular Imaging a Clinical Tool for Precision Oncology: A Review. JAMA Oncol 2017;3(5):695–701. Crossref, Medline, Google Scholar4. Kurland BF, Peterson LM, Lee JH, et al. Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by 18F-fluoroestradiol PET. J Nucl Med 2011;52(10):1541–1549. Crossref, Medline, Google Scholar5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783–792. Crossref, Medline, Google Scholar6. Giordano SH, Temin S, Chandarlapaty S, et al. Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2018;36(26):2736–2740. Crossref, Medline, Google Scholar7. Ulaner GA, Lyashchenko SK, Riedl C, et al. First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer. J Nucl Med 2018;59(6):900–906. Crossref, Medline, Google Scholar8. Ulaner GA, Carrasquillo JA, Riedl CC, et al. Identification of HER2-positive metastases in patients with HER2-negative primary breast cancer by using HER2-targeted 89Zr-pertuzumab PET/CT. Radiology 2020;296:370–378. Link, Google Scholar9. Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther 2010;87(5):586–592. Crossref, Medline, Google Scholar10. Gebhart G, Lamberts LE, Wimana Z, et al. Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol 2016;27(4):619–624. Crossref, Medline, Google ScholarArticle HistoryReceived: May 2 2020Revision requested: May 8 2020Revision received: May 8 2020Accepted: May 12 2020Published online: June 9 2020Published in print: Aug 2020 FiguresReferencesRelatedDetailsAccompanying This ArticleIdentification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CTJun 9 2020RadiologyRecommended Articles Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CTRadiology2020Volume: 296Issue: 2pp. 370-378PET of Fibroblast-Activation Protein for Breast Cancer Diagnosis and StagingRadiology2021Volume: 302Issue: 1pp. 48-49US Molecular Imaging Sensitively Captures Acute Ileitis Therapy ResponseRadiology2018Volume: 289Issue: 1pp. 101-102Nanotechnology for Cancer Imaging: Advances, Challenges, and Clinical OpportunitiesRadiology: Imaging Cancer2021Volume: 3Issue: 318F-16α-17β-Fluoroestradiol Binding Specificity in Estrogen Receptor–Positive Breast CancerRadiology2017Volume: 286Issue: 3pp. 856-864See More RSNA Education Exhibits The Utility Of 18F-FES PET In Breast Cancer.Digital Posters2021Theranostic Approach In Breast CancerDigital Posters2021Staging Breast Cancer: A Case Based ReviewDigital Posters2022 RSNA Case Collection Slow-growing cancerRSNA Case Collection2020Occult Breast CancerRSNA Case Collection2022Inflammatory breast cancerRSNA Case Collection2020 Vol. 296, No. 2 Metrics Altmetric Score PDF download