Short summary

Molecular evaluation represents a combination of molecular imaging, such as FDG-PET/CT and genomic profiling. We hypothesize that molecular evaluation allows an earlier detection of failure to respond to potentially toxic drugs in patients receiving breast cancer directed treatments. 

Rationale

Breast cancer is the most frequent malignant disease in Danish women with about 4,500 new cases per year and about 60,000 women living after a diagnosis of breast cancer. We have shown recently that the molecular whole body imaging with FDG-PET/CT has a higher accuracy than conventional imaging with CT and bone scintigraphy when diagnosing MBC; our results are in accordance with existing meta-analyses, and a recent review.

The gold standard for verifying MBC is a biopsy from a metastatic lesion, but treatment decisions are often based on the biomarker profile of the primary tumor, since it has been assumed to remain the same in the corresponding metastatic lesions. Our own data supported by a meta-analysis point towards discordances between the primary tumor and the corresponding metastasis ranging from 9% to 23%. While the spectrum of somatic mutations in primary breast tumors has been studied extensively, few studies have followed the mutational evolution from primary tumor to metastasis. The picture seems quite complex with new mutations in the asynchronous distant metastasis, the metastasis developing from a mutationally advanced subclone of the primary tumor, or from an early clone in the primary tumor followed by independent subsequent acquisition of additional mutations in both the primary tumor and in the metastasis.

It is essential to know the exact baseline stage of MBC in order to allow adequate evaluation of treatment response subsequently. Response evaluation criteria have traditionally been based on the morphological size of solid tumors as in the Response Evaluation Criteria in Solid Tumors (RECIST). We consider it important to include changes in metabolic activity for evaluation of treatment response, since metabolic changes occur before morphological changes can be detected. The PET response Criteria in Solid Tumors (PERCIST) is a new standardized method to assess quantitatively the metabolic tumor response as seen on FDG-PET/CT. A recent pooled analysis and review comparing the PERCIST to the RECIST criteria concluded that the PERCIST criteria seem to be more suitable for assessing tumor response than the RECIST criteria, but that the role of the PERCIST criteria needs to be validated in relevant clinical settings.

Monitoring response to therapy in skeletal metastases has been challenging because the RECIST criteria do not include changes in bony structures though the RECIST 1.1 accepts bone metastases with soft tissue masses measuring more than 10 mm as a target lesion. Up to 70% of patients with MBC present with bone involvement, characterized as osteolytic, osteblastic, or mixed lesions on CT. Soft tissue metastases in the bone marrow may be overlooked by conventional imaging, but magnetic resonance imaging (MRI) has shown high accuracy for diagnosing bone and bone marrow metastases. Molecular imaging with FDG-PET/CT and diffusion weighted MRI both have the potential to detect metabolic activity in all types of bone and bone marrow lesions, and therefore a combination of FDG-PET/CT and whole body MRI (WBMRI) may give valuable information in assessing metastatic processes in bone.

We hypothesize that molecular evaluation can provide a more accurate assessment of the metastatic spread than conventional methods and that molecular evaluation of response to breast cancer directed treatments allows an earlier detection of failure to respond to potentially toxic drugs.

The aims of our project are to address the following questions:

• Does molecular evaluation give a more accurate diagnosis of metastatic breast cancer (MBC) than conventional methods in terms of number and distribution of metastatic sites, and similarity to the primary tumor?
• Does molecular evaluation allow an earlier detection of failure to respond to treatment for MBC than conventional methods?
• Does molecular evaluation have the potential to lead to changes in the treatment plans made from conventional methods?

Description of the cohort

Part A: The study population will comprise all women referred to Odense University Hospital with suspected metastatic breast cancer (MBC). We expect to include 270 patients who will be examined with FDG-PET/CT and a blood sample for genomic profiling. If bone metastases are detected, the patients will proceed to MRI. All patients with suspected metastases on FDG-PET/CT or MRI will have a biopsy from a suitable lesion.

Part B: We expect to include 90 patients with biopsy-verified MBC (from part A). Patients will receive oncologic treatment according to national guidelines. Response to treatment will be evaluated by conventional CT criteria and compared to novel criteria according to FDG- PET/CT, and MRI.

Data and biological material

Tissue and blood will be collected from each woman for genomic profiling.

Furthermore, we will collect data from the woman's medical charts about her previous breast cancer, comorbidity, blood test and results from the scans.

Collaborating researchers and departments

Department of Oncology, Odense University Hospital

• Professor Marianne Ewertz, consultant, MD
• Associate professor Jeanette Dupont Jensen, MD, PhD
• PhD Student Marianne Vogsen, MD

Department of Nuclear Medicine, Odense University Hospital

• Associate Professor Malene Grubbe Hildebrandt, ph.d.

Department of Genetics, Odense University Hospital

• Professor Torben A. Kruse, PhD
• Associate Professor Mads Thomassen, Molecular biologist, PhD

Department of Pathology, Odense University Hospital

• Consultant Anne Marie Bak Jylling

Department of Radiology, Odense University Hospital

• Consultant Jon Asmussen

Department of Plastic Surgery, Odense University Hospital

• Consultant Katrine Søe

2 patient representatives

• Susanne Geneser
• Marie Lykke Rasmussen

Publications associated with the project

Vogsen M, Jensen JD, Christensen IY, Gerke O, Jylling AMB, Larsen LB, Braad PE, Søe KL, Bille C, Ewertz M, Hildebrandt MG. FDG-PET/CT in high-risk primary breast cancer-a prospective study of stage migration and clinical impact. Breast Cancer Res Treat. 2021 Jan;185(1):145-153. doi: 10.1007/s10549-020-05929-3. Epub 2020 Sep 12. PMID: 32920740.

Vogsen M, Jensen JD, Gerke O, Jylling AMB, Asmussen JT, Christensen IY, Braad PE, Thye-Rønn P, Søe KL, Ewertz M, Hildebrandt MG. Benefits and harms of implementing [18F]FDG-PET/CT for diagnosing recurrent breast cancer: a prospective clinical study. EJNMMI Res. 2021 Sep 22;11(1):93. doi: 10.1186/s13550-021-00833-3. PMID: 34553294; PMCID: PMC8458550.