Treatments for Hormone Sensitive Breast Cancer
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Oestrogen inhibiting Tamoxifen Citrate; an Antineoplastic Agent used to Treat Hormone Sensitive Breast Cancer
The Hormone Oestrogen (E) fuels female breast growth production at puberty. Within the breast of mature women, there are milk ducts called lobes which branch out to form lobules or acinus. Together, these are called the terminal lobular unit (TDLU) (Bullock, 2013, pp. 917-918).
Due to the various hormonal cycles that happen during a woman’s lifetime including, but not limited to child birth, Oestrogen and Progesterone levels are continuously fluctuating causing constant remodelling of the breast tissue. For example, menstruation causes the breast tissue to become increasingly vascular and encourages acinar tissue and ductal growth. Ancinar tissue converts to secretory glands through the release of progesterone at the luteal stage of the menstrual cycle. At this stage the terminal ducts are also dilated. (Craft. J, 2011, p. 951)
Mitotic stem cell division is increased within the TDLU during these stages leading to the development and renewal of the epithelial lining, increasing the chance of cell mutations in the TDLU an area where the majority of breast cancer (BC) occur (Craft. J, 2011, p. 983). Studies show a positive sign of hormone sensitive BC is the increased amount of Oestrogen receptors (ERα). The more Erαs in the affected cells, the greater affinity with E, therefore cell reproduction rises, leading to faster BC cell replication (Patani, 2014).
A benign tumor within the breast will remain localized and closely resembles normal epithelium cells within the tissue. Growth is at a slow rate within the TDLU, unlike a malignant (cancerous) tumor. The malignant tumor grows rapidly differentiating from the normal epithelial cell. It invades other tissue space and nearby blood and lymph vessels explaining why BCs easily spread into the lymphatic system and other areas of the reproductive system.
Risk factors affecting hormone sensitive breast cancer development in women are Post-menopausal obesity and the woman’s age at the birth of her first child, as connections between older mothers and obese post-menopausal women to ERα positive BC have been discovered (Yager & Davidson, 2006).
Tamoxifen Citrate (Trans-1-[4- (2-dimethylaminoethoxy) phenyl] 1, 2 -diphenyl-1 –butene) is a non-steroidal drug and an antineoplastic agent called a selective estrogen receptor modulator (SERM) (Marrero-Alonso et al., 2013). It is recommended as part of the treatment of hormone sensitive breast cancer due to its affinity with ERα acting as an antagonist to E, slowing cell division within the breast consequently stopping the progression of the BC (Bryant, 2011, p. 822).
Tamoxifen is given orally, absorbed in the gastro intestinal tract and metabolized in the liver by the enzymes CYP-450, 2D6 and 2C9. (Mandlekar, 2000 #20) Metabolites, produced are the ERα receptor binding 4-hydroxytamoxifen (OHT) and N-desmethyltamoxifen (DMT). Both have anti Oestrogen affects very close to their parent drug and cause apoptosis of BC cells. After dosing, various serum levels of Tamoxifen and metabolites were found within the lungs, liver ovaries and the endometrium and corpes luteum of the uterus, also in metastases within the brain and pancreas (Health Communication, 2004). Levels peak in about 3-6hours post a 10mg dose and reach a steady state around 4 weeks of therapy. They bind to albumin and are excreted mainly in the faeces so have a long half-life 5-7 days for Tamoxifen and 10-14 days for DMT (Health Communication, 2004).
Due to the metabolism of Tamoxifen and its metabolites, there is a risk of serum accumulation in prolonged treatment and or patients with poor hepatic function dosing regimens major need intermittent adjustment according to serum level findings. (Health Communication, 2004). Phenytoin lowers Tamoxifen metabolism and should therefore not be used concurrently with Tamoxifen for extended periods of time unless a therapeutic drug (Endoxifen) monitoring strategy is utilized as Tamoxifen will lose effectiveness. (Gryn, Teft, & Kim, 2014).
It has been found that Tamoxifen treatment in postmenopausal women is beneficial in reducing calcium loss by reducing apoptosis of osteoclasts thus sustaining bone density (Nakamura et al., 2007). This unfortunately is not the case in premenopausal women; in these cases osteoporosis is often increased with the use of Tamoxifen, dependent on whether chemotherapy had caused amenorrhea or not (Vehmanen, Elomaa, Blomqvist, & Saarto, 2006).
Tamoxifen use has been linked to increased episodes of deep vein thrombosis (VTE) in women using the drug in breast cancer prevention treatment (Decensi et al., 2005). Finally patients receiving Tamoxifen treatment for breast cancer long term ( > five years) are at greater risk of mortality from endometrial cancer than those who did not receive Tamoxifen (Jones et al., 2012).
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I hope I have created a better assignment this time round. I found the tutorial held on the 29/4/2014 very helpful as was the typed feedback sheet. I printed the latter out and sat it beside me while I typed out my assignment, along with the rubric and learning outcomes from the subject outline, referring to them often. The handwritten feedback was a little harder to decipher but I managed ok. My suggestion would be to type in an alternate colour e.g. Red for the feedback remarks on the actual assignment. I have learnt a lot from this assignment both about the subject and myself. I have incorporated more information into this assignment and have not included any quotes or paraphrasing from any of the texts I have used. The only similarities shown in turnitin were from my previous assignment. I have to say even with the setback I have enjoyed it.
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Decensi, A., Maisonneuve, P., Rotmensz, N., Bettega, D., Costa, A., Sacchini, V., . . . Veronesi, U. (2005). Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation, 111(5), 650-656. doi: 10.1161/01.cir.0000154545.84124.ac
Gryn, S. E., Teft, W. A., & Kim, R. B. (2014). Profound reduction in the tamoxifen active metabolite endoxifen in a patient on phenytoin for epilepsy compared with a CYP2D6 genotype matched cohort. Pharmacogenetics and Genomics, Publish Ahead of Print, 10.1097/FPC.0000000000000051.
Jones, M., van Leeuwen, F., Hoogendoorn, W., Mourits, M., Hollema, H., van Boven, H., . . . Swerdlow, A. (2012). Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: Pooled results from three countries. Breast Cancer Research, 14(3), R91.
Marrero-Alonso, J., Morales, A., García Marrero, B., Boto, A., Marín, R., Cury, D., . . . Díaz, M. (2013). Unique SERM-like properties of the novel fluorescent tamoxifen derivative FLTX1. European Journal of Pharmaceutics and Biopharmaceutics, 85(3, Part B), 898-910. doi: http://dx.doi.org/10.1016/j.ejpb.2013.04.024
Nakamura, T., Imai, Y., Matsumoto, T., Sato, S., Takeuchi, K., Igarashi, K., . . . Kato, S. (2007). Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell, 130(5), 811-823. doi: 10.1016/j.cell.2007.07.025
Vehmanen, L., Elomaa, I., Blomqvist, C., & Saarto, T. (2006). Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol, 24(4), 675-680. doi: 10.1200/jco.2005.02.3515
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