Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA.
BACKGROUND
Monitoring the effectiveness of therapy early and accurately continues to be challenging. We hypothesize that determination of Human Epidermal Growth Factor Receptor 2 (HER2) mRNA in malignant breast cancer (BC) cells by positron emission tomography (PET) imaging, before and after treatment, would reflect therapeutic efficacy.


METHODS
WT4340, a peptide nucleic acid (PNA) 12-mer complementary to HER2 mRNA was synthesized together with -CSKC, a cyclic peptide, which facilitated internalization of the PNA via IGFR expressed on BC cells, and DOTA that chelated Cu-64. Mice (n = 8) with BT474 ER+/HER2+ human BC received doxorubicin (DOX, 1.5mg/kg) i.p. once a week for six weeks. Mice (n = 8) without DOX served as controls. All mice were PET imaged with F-18-FDG and 48 h later with Cu-64-WT4340. PET imaging were performed before and 72 h after each treatment. Standardized uptake values (SUVs) were determined and percent change calculated. Animal body weight (BW) and tumor volume (TV) were measured.


RESULTS
SUVs for Cu-64-WT4340 after DOX treatment declined by 54% ± 17% after the second dose, 41% ± 15% after the fourth dose, and 29% ± 7% after the sixth dose, compared with 42% ± 22%, 31% ± 18%, and 13% ± 9% (p<0.05) for F-18-FDG. In untreated mice, the corresponding percent SUVs for Cu-64-WT4340 were 145% ± 82%, 165% ± 39%, and 212% ± 105% of pretreatment SUV, compared with 108% ± 28%, 151% ± 8%, and 152% ± 35.5%, (p<0.08) for F-18-FDG. TV in mice after second dose was 114.15% ± 61.83%, compared with 144.7% ± 64.4% for control mice. BW of DOX-treated mice was 103.4% ± 7.6% of pretreatment, vs. 100.1% ± 4.3% for control mice.


CONCLUSIONS
Therapeutic efficacy was apparent sooner by molecular PET imaging than by determination of reduction in TV.
Department of Radiology, Thomas Jefferson University, 1020 Locust Street, JAH 474, Philadelphia PA 19107, USA. Electronic address: bishnuhari.paudyal@jefferson.edu.
Bishnuhari
B
Paudyal
Kaijun
K
Zhang
Chang-Po
CP
Chen
Matthew E
ME
Wampole
Neil
N
Mehta
Edith P
EP
Mitchell
Brian D
BD
Gray
Jeffrey A
JA
Mattis
Koon Y
KY
Pak
Mathew L
ML
Thakur
Eric
E
Wickstrom
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D003301:Copper Radioisotopes; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000737:chemistry; D051379:Mice; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000378:metabolism; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D003301:Copper Radioisotopes; D004317:Doxorubicin; D006573:Heterocyclic Compounds, 1-Ring; D007334:Insulin-Like Growth Factor I; D020135:Peptide Nucleic Acids; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C508053:ERBB2 protein, human
Breast cancer; Copper-64; Doxorubicin; HER2; Peptide nucleic acid