Clinical Potential of Human Epidermal Growth Factor Receptor 2 and Human Epidermal Growth Factor Receptor 3 Imaging in Breast Cancer.

Breast cancer is the most common cancer in women worldwide, with approximately 12% of women in the United States developing invasive breast cancer in her lifetime.1 Although breast cancer has come a long way in regards to treatment options and overall survival, there are still challenges that occur mostly from intratumoral heterogeneity2 and metastatic disease.3 While significant research has emerged to identify biological processes leading to breast cancer,4 selecting patients that would benefit from targeted therapies is still a major hurdle in the field. Non-invasive tools to stratify patients and facilitate precision medicine are needed to address this issue.5–7 Although breast cancer is typically diagnosed and staged via three main biomarkers, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2),8 there are other biomarkers of interest that are relevant and may be beneficial to the clinical outcome of breast cancer. Reports of clinical benefit from HER2-targeted therapy in patients with a primary HER2-negative tumor have facilitated to spearhead the concept behind HER2-targeted molecular imaging for unsuspecting metastasis in breast cancer.9–10 An additional biomarker of interest includes human epidermal growth factor receptor 3, or HER3.11 HER3 overexpression has been linked with poor prognosis in multiple cancer subtypes including breast, which has driven interest in HER3 as potential target for both imaging and therapy. Additionally, emerging resistance to HER2-targeted therapy has driven the need to explore additional targets for both imaging and therapy.11 The HER family in general has been extensively studied in breast cancer,12 and there are many HER2-targeted agents for therapy and molecular imaging,13–15 and strategies to target HER3 are also on the rise with clinical trials.16–17 Molecular imaging, particularly with tracers used in positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have the ability to non-invasively detect heterogeneity between primary tumors and metastases in breast cancer.6, 18 PET and SPECT-based measurement of the HER2 and HER3 expression in breast cancer offers several advantages over repeated biopsies in patient cohorts. Several groups have developed antibody, affibody, and nanoparticle-based radioligands for PET imaging preclinically and clinically,19–22 many of which include radiotracers used to image HER2 and HER3 in breast cancer.13, 23 Pairing these targeting moieties with longer-lived radioisotopes such as zirconium-89 (89Zr, t1/2 = 78 h) for PET, along with lutetium-177 (177Lu, t1/2 = 6.7 days) and indium-111 (111In, t1/2 = 67 h) for SPECT can be used to match the biological half-life of antibodies in vivo (t1/2 ~72 h for typical full-length antibodies).24 Isotopes like copper-64 (64Cu, t1/2 = 12 h) or technium-99m (99mTc, t1/2 = 6 h) can be used in PET and SPECT, respectively, for both full length and antibody fragments, as well as affibodies.25–27 Antibody fragments and affibody molecules are often labeled with shorter-lived isotopes such as gallium-68 (68Ga, t1/2 = 68 min) or fluorine-18 (18F, t1/2 = 110 min) to pair appropriately with shorter biological half-lives in vivo.28–31 Many of the PET and SPECT imaging tracers that have made it to the clinic (in Phase I/II trials) to detect HER2-positive breast cancer and metastases, are summarized in our previous review.15 This current review seeks to communicate an update about the current clinical trials for both HER2 and HER3-targeted imaging, which are outlined in Table 1. The current clinical radiotracers used to image HER3+ and HER2+ breast cancers are review within. Table 1 Summary of current clinical trials with PET and SPECT radiotracers targeting HER2 and HER3-positive breast cancer in 2017. BC: breast cancer. MBC: metastatic breast cancer. IMPACT: IMaging PAtients for Cancer Drug selection.