Imaging in Metastatic Breast Cancer Clinical Trials: Overcoming Specific Challenges

Background

Metastatic Breast Cancer (MBC) predominantly spreads to the bones, followed by lung, liver, and brain. The metastatic spread is different between MBC subtypes. Hormone Receptor (HR) positive/ human epidermal growth factor receptor 2 (HER2) negative tumors and both HER2 positive subtypes present with higher rates of liver, brain, and lung metastases. Whereas Triple-Negative Breast Cancer (TNBC) is associated with an even higher rate of brain metastases but a lower rate of bone metastases.

Early Breast Cancer (EBC) oftentimes follows a (neo)adjuvant treatment approach, which is reflected in different imaging modalities being used. During the adjuvant treatment the focus is to identify disease recurrence.

Therefore, it is imperative to ensure the appropriate imaging modality and anatomical coverage is selected for the clinical study.

Mammography is a planar, structural imaging technique and currently the diagnostic gold standard. Its high specificity and sensitivity make it an ideal modality to examine local disease recurrence.

Breast ultrasound is oftentimes used in conjunction with mammography to support the diagnosis in women with dense breast tissue.

Interpreting Breast Cancer Changes during Clinical Trials

To evaluate drug efficacy in clinical trials evaluating breast cancer, Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI) are the modalities of choice to assess local disease status as well as distant metastases (Figure 1). They are also the suggested imaging modalities to perform a RECIST 1.1 evaluation.

Due to its higher sensitivity, breast MRI is a good tool for EBC and adjuvant studies to reliably detect disease recurrence. Patients with known or suspected brain metastasis should undergo brain imaging, preferably with MRI. 

Figure 1: Liver metastases from breast cancer. Axial contrast-enhanced CT scans in different patients shows multiple low-attenuation hepatic metastatic lesions. (A) Large measurable lesion is seen in segment VII of liver and smaller lesions are seen in segment IV and left lobe of liver. (B) Large lesion seen in segment VIII with smaller lesion seen adjacent to this dominant lesion.

In addition, functional and metabolic imaging should be considered. Bone scintigram, such as 99mTC bone scan is used to evaluate bone metastases. Based on our experience, bone scans showing the healing of bone metastases can mimic progression, and thus correlative bone imaging may be needed. 

While bone scan is a sensitive technique for evaluation of bone metastases, it lacks specificity (Figure 2). Thus, accompanying imaging such as radiographs, CT or MRI are recommended to differentiate bone metastases from benign processes, such as degenerative disease, infection, healing fractures or metabolic disorders. 

Specific language in the Independent Review Charter (IRC) will address when to consider developing bone scan lesions as new lesions (malignant) with or without correlation with accompanying imaging, as applicable. PET-CT or PET-MRI provides a holistic view of structural and metabolic changes.

Figure 2: Examples of a bone scan of poor quality (A) and a bone scan of less-than-ideal quality, although evaluable (B).

Best Practices

In general, the imaging modality used at screening shall be kept the same for post-baseline timepoints to ensure consistency and avoid variability in the measurement and assessment of disease.

Prior and/or on-study radiotherapy can make lesion assessment challenging for the independent radiologist reviewer, since the treatment effect of radiotherapy must not be mistaken for drug effect. Specific RECIST 1.1 modifications are needed to evaluate response in such patients and must be established in the IRC.

Lung Metastases

The appearance and size of lung metastases vary greatly depending on the CT image display (window settings). The reviewer training must define the best window settings to use for consistent lesion evaluation and measurements across timepoints. Additionally, specific assessment guidelines may be defined to allow a more accurate differentiation between benign pulmonary nodules and pulmonary metastases.

For instance, benign pulmonary nodules are typically single and show calcification whereas pulmonary metastases are usually multiple and don’t show calcification. Pleural effusions are also frequently seen in breast cancer and may also be due to treatment side effects. Specific language in the IRC will address when to consider baseline pleural effusions as non-target lesions and developing pleural effusions as new lesions (malignant).

Brain Metastases

Brain metastases originating from breast cancer vary in size, shape, and contrast enhancement patterns. They can appear as solid, uniformly enhancing lesions or with ring enhancement and central necrosis with different amounts of perilesional edema (Figure 3). Leptomeningeal carcinomatosis is more often seen in TNBC patients and presents as a nodular or diffuse enhancement of the leptomeninges on the brain surface.

 Figure 3: Multiple brain lesions with ring enhancement or solid enhancement in both hemispheres

Independent review by an oncologist following the independent radiology review can be useful in interpreting clinical data in relation to the radiology determinations. For example, further evaluation of pleural effusions with available cytology results may indicate a benign cause for the effusion. An independent oncologist review can be useful in incorporating clinical data into the response assessment.

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