Disease pathophysiology
Definition of breast cancer
Breast cancer is a malignant growth of cells in the breast. This type of cancer arises in the milk-producing glands when cells begin to divide in an uncontrolled way, forming a tumor. The most common neoplasm in breast cancer is the adenocarcinoma of the cells covering the terminal lobular unit (American Cancer Society, 2016; Stephan, 2016).
Prevalence of breast cancer
Breast cancer is the most common invasive cancer to affect women in North America, with more than 200,000 new cases each year, and worldwide, counting up more than 1,200,000. It is the second cause of cancer death in women. Worldwide, in 2012, nearly 1.7 million new breast cancer cases were diagnoses (World Cancer Research Fund International [WCRF], n.d). In 2013, around 3,053,450 women had breast cancer in the United States, and by 2015 the expected number of new reported breast cancer was approximately 231,800, which represents 29% of all cancers (Ban & Godellas, 2014; Lumachi, Santeufemia & Basso, 2015). By this year, 2016, new invasive breast cancer cases estimation is around 246,660 in women and 2,600 in men in the U.S (Breastcancer.org, 2016).
In 2012, Northern America and Oceania had the highest rate of breast cancer. On the other hand, Asia and Africa had the lowest incidence (WCRF, n.d). Siegel et al. (2012) reported a median age of 61 for breast cancer diagnosis, being a 20% of the breast cancers in women younger than 50 years and a 40% among women aged 65 years or more. Diagnoses of more than 60% of breast cancers are at a localized stage.
Pathophysiology of breast cancer and differences between hormone positive and hormone-negative breast cancer
Damage of DNA and genetic mutations are related to breast cancer. Also, it has been linked to estrogen exposure. Some genes, including BRCA1, BRCA2 and P53, are associated to the increase of risk of breast cancer. Immune system failure and changes in growth factors can lead to this type of cancer. Breast cancer can have receptors for hormones estrogen and progesterone or not. These receptors are proteins that take some signals from the hormone in order to tell the cells to grow. Cancer cells may have neither, one, or both estrogen and progesterone receptors. Breast cancers that have estrogen receptors are referred to as estrogen-receptor-positive (ER +) cancers, and those having progesterone receptors are called PR-positive cancers (American Cancer Society, 2016).
Hormone positive breast cancer, also called hormonal breast cancer, requires a hormonal supply (estrogen or progesterone) to develop, proliferating in response to hormone stimulation. They can be treated using some inhibitors. On the other hand, in hormone-receptor-negative cancer hormonal therapy is improbable to work (Bae et al., 2015).
Breast cancer in post-menopause woman and in pre- menopause women what is the differences (what happened for estrogen production).
Breast cancer is not caused by menopause, but age is important in cancer development. Particularly, in women who experience menopause after age of 55, an increased risk of this type of cancer is reported. Hormonal changes due to the onset of menopause seem to play an important role in causing breast cancer. In that way, pre-menopausal women do not have the same hormonal risk factors as do the post-menopausal ones. Higher blood estrogen levels increase breast cancer risk in premenopausal women (Surkasula, Nagarjunapu & Raghavaiah, 2014). A positive relationship between blood levels of estrogens and the risk of breast cancer has been reported (Colditz, 1998)
Evolution of Receptor (Biological Target)
Inhibition of estrogen receptors (mechanism, advantages, side effects, previous drugs that work on this receptor)
The mechanism of inhibition of estrogen receptors can be explained by the selective estrogen receptor modulators (SERMs). Drugs, such as, tamoxifen, raloxifene and toremifene, act as competitive inhibitors of estrogen, binding to estrogen receptors having agonist and antagonist activity, and blocking the signal at the estrogen receptor level (Cosman, 1999). These compounds exhibit tissue-specific estrogenic activity; in the case of breast tamoxifen, it selectively blocks ER signaling and inhibits the proliferation of ductal cells. Another group of estrogen receptor regulators are down-regulators (SERDs), having a different structure and causing down-regulation and degradation of the estrogen receptors, exhibiting exclusively anti-estrogen effects (Lumachi, Santeufemia & Basso, 2015).
Some advantages of these inhibitors are the reduction of long term mortality in people having breast cancer and treated with these compounds, and limited age-related side effects. Tamoxifen benefits only women with estrogen receptor positive breast cancer and is the drug most extensively used when a SERM is required both in pre and postmenopausal women (Lumachi, Santeufemia & Basso, 2015). It also has a bone protective effect, helping in the bone mineral density in postmenopausal women (EBCTCG, 2015).
Side effects related to these inhibitors are some vascular and endometrial effects. It has estrogenic activity in other tissues, such as the uterus producing vaginal bleeding and endometrial hyperplasia. They also cause thromboembolic disease, fatigue, hot flashes, and vaginal dryness. Other SERMs have been developed, including, fulverstrant, toremifene and raloxifene, with fewer side effects than tamoxifen (Lumachi et al., 2013).
Inhibition of aromatase enzyme (mechanism, advantages, side effects, previous drugs that work on this receptor).
The aromatase enzyme canalizes the estrogen’s biosynthesis for the formation of progesterones and androgens. This enzyme activity is blocked by the aromatase inhibitors (AIs) reducing levels of circulating estrogen in postmenopausal women. In premenopausal women, when the ovary is functionally active, gonadotropin secretion is increased and estrogen is produced, being aromatase inhibitors ineffective. Exemestane, an AI, acts as a false substrate for aromatase suppressing estrogens (Lumachi et al, 2013).Advantages of AIs demonstrated an improved survival in patients with advanced estrogen receptor positive breast cancer, reducing the recurrence of the disease (Lumachi et al, 2013).Aromatase inhibitors produce some side effects, such as, increased risk of rash, arthralgia, diarrhea, and effects on cognitive functions. (Lumachi et al, 2013). Bone fracture is a concern in the use of AIs (EBCTCG, 2015).
Which of those two receptors is better to use in post menopause women and why?
Aromatase enzyme inhibition is better to use in post menopause women. Aromatase inhibitors reduce recurrence rate compared with tamoxifen (EBCTCG, 2015). The risk of thromboembolic events and vaginal bleeding is lower using AIs in contrast to tamoxifen. A meta-analysis comparing tamoxifen and AIs demonstrated the decrease of risks of endometrial cancer and venous thrombosis. Third generation AIs, such as exemestanes, anastrozole and letrozole, are associated with better survival than using SERMs. Also, adjuvant treatment, either as using AIs as upfront therapy or as a sequential treatment after tamoxifen, has been effective in postmenopausal women having ER+ cancer (Lumachi et al, 2013). Great reduction of estrogen concentration in postmenopausal women is found when aromatase inhibitors are used (EBCTCG, 2015).
Reference List
American Cancer Society. (2016). How is breast cancer classified? Retrieved from http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-classifying
Ban, K. A. & Godellas, C. V. (2014). Epidemiology of Breast Cancer. Surgical oncology clinics, 23(3), 409–422. DOI: http://dx.doi.org/10.1016/j.soc.2014.03.011
Bae, S. Y., Kim, S., Lee, J. H., Lee, H., Lee, S. K., Kil, W., HNam, S., J. (2015). Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer. BMC Cancer, 15, 138. DOI: 10.1186/s12885-015-1121-4
Breastcancer.org (2016). U.S. Breast Cancer Statistics. Retrieved from http://www.breastcancer.org/symptoms/understand_bc/statistics
Cosman, F. & Lindsay, R. (1999). Selective estrogen receptor modulators: clinical spectrum. Endocrine Reviews, 20(3), 418-434. http://dx.doi.org/10.1210/edrv.20.3.0371
Colditz, G. A. (1998). Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. Journal of the National Cancer Institute, 90(11), 814-823.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). (2015). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. The lancet, 386, 1341-1352. Retrieved from http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)61074-1.pdf
Lumachi, F., Brunello, A., Maruzzo, M., Basso, U., & Basso, S.M.M. (2013). Treatment of Estrogen Receptor-Positive Breast Cancer. Current Medicinal Chemistry, 20, 596-604. DOI: 10.2174/092986713804999303
Lumachi, F., Santeufemia, D. A., & Basso, S. M. (2015). Current medical treatment of estrogen receptor-positive breast cancer. World Journal of Biological Chemistry, 6(3), 231–239. http://doi.org/10.4331/wjbc.v6.i3.231
Siegel, R., De Santis, C., Virgo, K., Stein, K., Mariott A., Smith, T., Ward, E. (2012). Cancer Treatment and Survivorship Statistics, CA. Cancer Journal for Clinicians 62(4), 220-241. http://onlinelibrary.wiley.com/doi/10.3322/caac.21149/epdf
Stephan, P. (2016). What is Breast Cancer? Retrieved from https://www.verywell.com/what-is-breast-cancer-430090
Surakasula, A., Nagarjunapu, G. C., & Raghavaiah, K. V. (2014). A comparative study of pre- and post-menopausal breast cancer: Risk factors, presentation, characteristics and management. Journal of Research in Pharmacy Practice, 3(1): 12–18. http://doi.org/10.4103/2279-042X.132704
World Cancer Research Fund International (WCRF) (n.d.) Breast cancer statistics. Retrieved from http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breast-cancer-statistics
