Application of radioisotope imaging and therapy in patients with breast carcinomas that express the sodium iodide symporter gene.
MD thesis, University of Glasgow.
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The Sodium Iodide Symporter (NIS), which is located in the basolateral membrane of the thyroid follicular cell, catalyses an active transport mechanism allowing Iodide, an essential component of the thyroid hormones Tri-iodothyronine(T3) and Thyroxine(T4), to accumulate in the thyroid gland. Differentiated thyroid cancers retain the appearance and function of normal thyroid cells, and can, therefore, trap iodine. Radioiodide scintigraphy and therapy are based on the uptake of radioiodide by NIS in thyroid tissue, which can concentrate all isotopes of iodine.
Breast cancer is the most common type of cancer in women in the UK, and is the second most common cause of cancer-related death in women in the UK. This situation remains true in Scotland, with breast cancer representing 27.5% of all female cancers. Despite a reduction in mortality figures between 1994 and 2004 of 18%, five year survival in Scotland remains only 80.2% for patients diagnosed between 1997 and 2001. When breast cancer recurs and becomes metastatic it is treatable, but not curable. Median overall survival of patients with metastatic disease remains poor, and is currently between one and two years. It is clear that metastatic breast cancer remains a challenging clinical issue and novel treatments are required.
Radionuclides play an important part in the management of malignancy, including prostate cancer, neural crest tumours, and thyroid cancers. There is evidence that there may be a role for radionuclide therapy in breast cancer via the NIS mechanism. This was first suggested by Tazebay's landmark work in 2000, which demonstrated that a significant proportion (87%) of breast cancers contained detectable NIS protein by immunohistochemistry(IHC).
Tumour samples from patients with breast cancer were analysed by immunohistochemistry and ribonucleic acid(RNA) analysis, and this was correlated with functional activity of the NIS protein, by scintigraphic scanning of patients with metastatic breast cancer.
Twenty-four patients had a Tc99m Pertechnetate scan; 20 patients had their RNA analysed; 22 patients had IHC performed on their tumour samples. NIS was detected only in the control Graves thyroid RNA and paraffin embedded cells extracted from a NIS expressing cell line. Breast tumour sample RNA did not demonstrate NIS. By IHC, 15 cases were defined as truly immunopositive, with the criteria for true positivity being a Histoscore of > 150, or demonstration of membrane staining. Seven cases were negative by the above criteria. Tc99m Pertechnetate uptake was observed in 11 of 24 patients who were scanned ie 46%.
Of these 15 patients with positive expression of NIS in their breast cancer tissue sample, as measured by immunohistochemistry, 14 cases were also scanned. Of these, eight patients(57%)demonstrated uptake of Tc99m Pertechnetate on scintigraphy ie were true positives; six did not, ie their screening test (IHC) had incorrectly predicted positive uptake on subsequent scanning (false positive screening). Therefore, a positive predictive value of 57% was observed when using IHC as a screening test for detecting those patients who would go on to have a positive scan. In contrast, six patients had negative NIS expression by IHC, and no uptake on scintigraphy, ie true negatives. Only one patient had a false negative screening IHC result. A negative predictive value of 86% was seen when using immunohistochemistry as a screening test for detecting those patients who would have a negative scan. Sensitivity was 88%, with a specificity of 50%.
This data has shown that the prevalence of patients with metastatic breast cancer expressing NIS on IHC is relatively high (68%), when compared with one other published study of similar patients. Also, it has been demonstrated that a high proportion of NIS IHC positive patients who were scanned (57%) demonstrated uptake of Tc99m Pertechnetate in breast cancer primary or metastases.
It can be concluded that IHC does act as a useful screening test for those who may ultimately benefit from radioisotope treatment. The most appropriate radioisotope for therapy remains to be determined.
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