An Approach to Breast Cancer Diagnosis via PET Imaging of Microcalcifications Using (18)F-NaF.
Current radiologic methods for diagnosing breast cancer detect specific morphologic features of solid tumors or any associated calcium deposits. These deposits originate from an early molecular microcalcification process of 2 types: type 1 is calcium oxylate and type II is carbonated calcium hydroxyapatite. Type I microcalcifications are associated mainly with benign tumors, whereas type II microcalcifications are produced internally by malignant cells. No current noninvasive in vivo techniques are available for detecting intratumoral microcalcifications. Such a technique would have a significant impact on breast cancer diagnosis and prognosis in preclinical and clinical settings. (18)F-NaF PET has been used solely for bone imaging by targeting the bone hydroxyapatite. In this work, we provide preliminary evidence that (18)F-NaF PET imaging can be used to detect breast cancer by targeting the hydroxyapatite lattice within the tumor microenvironment with high specificity and soft-tissue contrast-to-background ratio while delineating tumors from inflammation.


METHODS
Mice were injected with approximately 10(6) MDA-MB-231 cells subcutaneously and imaged with (18)F-NaF PET/CT in a 120-min dynamic sequence when the tumors reached a size of 200-400 mm(3). Regions of interest were drawn around the tumor, muscle, and bone. The concentrations of radiotracer within those regions of interest were compared with one another. For comparison to inflammation, rats with inflamed paws were subjected to (18)F-NaF PET imaging.


RESULTS
Tumor uptake of (18)F(-) was significantly higher (P < 0.05) than muscle uptake, with the tumor-to-muscle ratio being about 3.5. The presence of type II microcalcification in the MDA-MB-231 cell line was confirmed histologically using alizarin red S and von Kossa staining as well as Raman microspectroscopy. No uptake of (18)F(-) was observed in the inflamed tissue of the rats. Lack of hydroxyapatite in the inflamed tissue was verified histologically.


CONCLUSIONS
This study provides preliminary evidence suggesting that specific targeting with (18)F(-) of hydroxyapatite within the tumor microenvironment may be able to distinguish between inflammation and cancer.
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee.
George H
GH
Wilson
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, Tennessee Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee.
John C
JC
Gore
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, Tennessee Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Thomas E
TE
Yankeelov
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
Stephanie
S
Barnes
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
Todd E
TE
Peterson
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee.
Jarrod M
JM
True
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
Sepideh
S
Shokouhi
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, Tennessee Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
J Oliver
JO
McIntyre
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
Melinda
M
Sanders
Department of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
Vandana
V
Abramson
Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, Tennessee.
The-Quyen
TQ
Ngyuen
Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, Tennessee.
Anita
A
Mahadevan-Jansen
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee n.tantawy@vanderbilt.edu.
Mohammed N
MN
Tantawy
D000818:Animals; D001943:Breast Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000150:complications*; D045744:Cell Line, Tumor; D017886:Durapatite / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography; D012969:Sodium Fluoride
D005462:Fluorine Radioisotopes; D012969:Sodium Fluoride; D017886:Durapatite
18F-NaF; 18F−; MDA-MB-231; PET; hydroxyapatite; breast cancer; calcium oxalate; microcalcification