According to the Canadian Cancer Society, it is estimated that there were 28,600 new
cases of breast cancer and 5,500 deaths due to the disease in Canada in 2022. Early
stage, estrogen receptor-positive (ER+) tumor lesions are normally treated with
resection, chemotherapy, and then hormone therapy and have the best prognosis for cure1.
However, cases with metastases2, receptor-negative (ER-)3, and/or recurrence4 have a poor
outcome and increased mortality. However, overexpression of the pro-oncogene Human
Epithelial growth factor Receptor 2 (HER2), with or without ER expression, is linked to
more aggressive cancers with poor prognoses5. Thus, ER and HER2 status are two of the
most important prognostic factors for breast cancer and are routinely monitored on biopsy
and tumor resection samples in pathology. HER2 status is also important to know in a
range of cancers, including esophageal,6 gastric,7 ovarian,8 endometrial,9 and lung.10
However, it has been reported that in breast cancer patients with HER2 overexpression
treated with a combination of chemotherapy and Herceptin (trastuzumab), a HER2-targeted
antibody, the status of a potential recurrence will be HER2- in 43% of cases.11 A
receptor status mismatch has been found between primary lesions and metastatic sites in
15% of patients for HER2 at initial workup.12-13 These data show that a substantial
number of metastatic and/or recurrent breast cancers have heterogeneous disease, for
which conventional primary and locoregional biopsy methods will fail to identify the
optimal treatment plan and provide an accurate prognosis.
Although the feasibility of taking biopsies from suspected metastatic sites has been
demonstrated to monitor the status of distal lesions14, it is difficult or impossible to
take biopsy samples from all known and suspected sites for each patient, especially
without knowing the precise metastatic status of each patient. This finding therefore
highlights the need for a pan-body and non-invasive method of assessment and detection of
HER2 for better cancer management and better use of targeted therapies.
Several medical imaging modalities allow the detection and monitoring of whole-body
cancers. Among these, [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)
is routinely used for the initial assessment and staging16 as well as for monitoring of
cancer treatment15, and this with high sensitivity and precision. On the other hand, FDG
is not a tumor-specific tracer, and its uptake only reflects the relative avidity of a
given tissue for glucose. Consequently, the physiological distribution and/or the
presence of non-cancerous pathologies can reduce tumor contrast, even mask certain
lesions, or lead to false positives17.
Trastuzumab and other antibodies targeting HER2 (Kadcyla, pertuzumab, etc.) are commonly
used in the clinic and are very effective immunotherapies for the treatment of these very
aggressive and previously very difficult to treat tumors. A few groups have already
radiolabeled trastuzumab with zirconium-89 ([89Zr]-DFO-trastuzumab), and animal18 and
human19 PET imaging studies have been successfully conducted. In 2016, the first data
derived from PET imaging of human dosimetry and biodistribution of [89Zr]-DFO-trastuzumab
were reported by an American group20,24. Recently, our research group has also succeeded
in producing [89Zr]-DFO-trastuzumab with a better molar activity (~25 MBq/nmol) than that
reported elsewhere so far21-22. A preclinical protocol of PET imaging with 4FMFES (an ER
tracer) and [89Zr]-DFO-trastuzumab in succession on mice bearing ER+ and HER2+ tumors was
developed, allowing the detection and identification with high contrast of lesions with
different ER and HER2 status21-22. No side effects were detected during the preclinical
procedures, indicating that the formulation is adequate. Building on these results and
the expertise developed during these projects, we aim to transpose [89Zr]-DFO-trastuzumab
PET imaging into the clinic during a phase II study on a cohort of patients with HER2-low
cancer (IHC of HER 2 to 1+ or 2+ out of 3)25. More specifically, this imaging protocol
aims to assess whole-body HER2 status26 and thus be able to detect cases with
heterogeneous disease, in addition to standard locoregional biopsies. Thus, a clinical
phase II focusing on the evaluation of a PET/CT protocol using [89Zr]-DFO-trastuzumab in
succession to clinically prescribed FDG on patients will be conducted in order to produce
the equivalent of a whole body biopsy of HER2 by imaging.