99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer.
Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo.


METHODS
Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry.


RESULTS
Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min.


CONCLUSIONS
(99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.
Mubashar
Muhammad
M
Department of Imaging, Hammersmith Hospital, London, United Kingdom.
Harrington
Kevin J
KJ
Chaudhary
Khurram S
KS
Lalani
El-Nasir
el-N
Stamp
Gordon W
GW
Sinnett
Dudley
D
Glass
Daphne M
DM
Peters
A Michael
AM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000187:drug effects*; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001940:Breast / Q000000981:diagnostic imaging; D001943:Breast Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000188:drug therapy; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D017256:Technetium Tc 99m Sestamibi; D017312:Toremifene / Q000627:therapeutic use*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018931:Antineoplastic Agents, Hormonal; D019275:Radiopharmaceuticals; D020845:Selective Estrogen Receptor Modulators; D017312:Toremifene; D017256:Technetium Tc 99m Sestamibi