PES NWI: “PRACTICE ENVIRONMENT SCALE OF THE NURSING

Selective estrogen receptor modulators (SERMs) have been clinically approved for the treatment of breast cancer for four decades. Initially discovered as a non-steroidal anti-estrogen compound and used unsuccessfully as a contraceptive, tamoxifen was first clinically tested in metastatic breast cancer in 1971 and subsequently approved in 1977400. The success with tamoxifen motivated the synthesis of similar drugs, with the discovery of raloxifene in 1982401_{. Subsequently,} studies in the 1980s, after advances in cloning of the ERα gene, suggested tamoxifen and raloxifene worked by selectively modifying ER signaling400. Investigation of tamoxifen for the chemoprevention of breast cancer began in 1985, with eventual approval of tamoxifen for breast cancer risk reduction in 1998400,402. Raloxifene was approved for the treatment and prevention of osteoporosis in postmenopausal women in 1998403_{. Subsequently, clinical trials demonstrated} equivalence between raloxifene and tamoxifen in breast cancer risk reduction, granting raloxifene a second approval for the chemoprevention of breast cancer in 2007404–406. Importantly, raloxifene is not approved for the treatment of breast cancer, only for risk reduction in postmenopausal women406,407.

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The three most pertinent sites of action for SERMs are those in which estrogen signaling plays a significant role in organ pathophysiology, namely in the breast, the bone, and the uterus. Importantly, tamoxifen and raloxifene exhibit different tissue sites of action. While tamoxifen and raloxifene act as anti-estrogens in breast carcinoma and as pro-estrogens in the bone, only tamoxifen acts as a pro-estrogen in the uterus408,409. Thus, while both tamoxifen and raloxifene share similar effects on breast cancer and osteoporosis prevention, only tamoxifen increases the clinical risk for endometrial carcinoma407–409_.

The tissue dependence of SERM activity is intimately involved with their ability to influence estrogen receptor conformation and binding to coregulatory molecules. While the SERMs bind in the same pocket as estradiol, the binding of tamoxifen, raloxifene, and estradiol induce different conformations of the estrogen receptor409–411. Additionally, the interaction of coactivators and corepressors with ligand-bound estrogen receptor is dependent on the ligand. Coregulator interactions with the estrogen receptor are mediated through the AF1 and AF2 domains, which are regulated by MAPK activity and estradiol binding, respectively412. Importantly, SERMs primarily alter signaling through the AF2 domain and exhibit variable effects on the AF1 domain responsible for estrogen agonistic activity413. For example, SRC-1 is a coactivator that mediates estrogen agonistic effects of both estradiol and tamoxifen but is required for agonist activity of the latter414. Similarly, the corepressor SMRT can reduce the agonist activity of tamoxifen but not estradiol414. Moreover, the relative abundance of the estrogen receptor isoforms ERα and ERβ can guide the activity of the SERMs in affecting gene transcription415_. Finally, the agonist/antagonist effects of SERMs can be influenced by intracellular signaling networks, such as protein kinase A416_{. In summary, the mechanism of action of SERMs depends}

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on the relative abundance of the target receptor isoforms, presence of coregulators, and activation of intracellular signaling networks.

Mechanisms of resistance to SERMs can be classified as either intrinsic or acquired. Intrinsic resistance to SERMs is most often due to crosstalk from other signaling pathways or differences in drug metabolism. For example, HER2 overexpression results in increased estrogen- independent ER signaling, making tumors resistant to de novo SERM treatment417–419. Intrinsic resistance to tamoxifen can also be observed in patients with polymorphisms in CYP2D6 and CYP3A4, the two CYP450 isozymes responsible for metabolic activation of tamoxifen418,419. Acquired resistance to tamoxifen often involves alterations in the expression of estrogen receptor isoforms, coregulators, and activity of other intracellular signaling networks. Increased expression of ERβ and loss of ERα have been observed in tamoxifen-resistant breast cancer420,421_{. Similarly,} mutations in ERα are common drivers of resistance420,422. Moreover, expression of SRC3, an ERα co-activator expressed in over 50% of breast tumors, can increase the estrogen agonist effects of tamoxifen, which leads to resistance412. Finally, overexpression of HER2 or EGFR act as a mechanisms of acquired resistance to tamoxifen by enhancing Erk1/2 and Akt activity420,423.

Tamoxifen is administered orally and produces peak serum levels after 3-6 hours and steady state levels after 4 weeks424_{. Tamoxifen is extensively bound to albumin (~98%), which} results in a long elimination half-life of 7 days425. Tamoxifen is extensively metabolized by the CYP450 system, which is required for its activation. The two primary active metabolites of tamoxifen are endoxifen and 4-hydroxytamoxifen, with the former found at more than 10-fold higher concentrations in patient serum426. The two main CYP450 isoforms that are responsible for tamoxifen metabolism are CYP2D6 and CYP3A4424_{. Tamoxifen is eliminated primarily by biliary} excretion, with polar conjugates of tamoxifen and its metabolites formed through glucuronidation,

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accounting for 75% of the excreted drug426. The most common toxicities with tamoxifen are a 2-5 fold increase in uterine cancer, a 2-3 fold increase in thromboembolic disease (only seen in postmenopausal women), hot flashes, and vaginal discharge407,427. Additionally, patients receiving tamoxifen are at a slightly greater risk for the formation of cataracts407,427.

Raloxifene undergoes significant first pass metabolism by glucuronidation, resulting in only 2% of the drug dose reaching the plasma428. Similar to tamoxifen, raloxifene is extensively plasma protein bound (95%), yet has a much lower elimination half-life at 27.7 hours428_{. The} metabolism of raloxifene is primarily accomplished by glucuronidation without involvement of the CYP450 ensemble428. Similar to tamoxifen, raloxifene primarily undergoes biliary excretion. Raloxifene has fewer adverse effects than tamoxifen, yet still results in a 3 fold increase in risk for thromboembolic disease409.