Endocrine therapy for breast cancer: carcinogenic effects of tamoxifen

In what form is it produced?

The drug Tamoxifen is available in the form of coated tablets with a total mass of active substance of 10 and 20 mg.

The tablets are placed in plastic bottles, which are packed in cardboard boxes. The drug is dispensed only with a prescription from the attending physician. The average cost of 1 package of Tamoxifen is 1200 rubles.

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Short Wiklad

The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists' Group Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial Lancet 2002; 359:2131-39

*In Ukraine, the drug is registered by the Astra Zeneca company under the name ARIMIDEX. **Completed. The cob is at the forefront of the magazine.

Side effects

The frequency of subsequent side effects is shown in the table. 5. In all trials, there was no obvious difference between the groups for tamoxifen and anastrozole. However, when substituted with tamoxifen monotherapy, anastrozole led to a significant change in the frequency of hot flashes, vision and bleeding from the kidneys, ischemic disorders of cerebral blood flow, episodes of venous thromboembolism (including with thrombosis of the veins) and endometrial cancer. For comparison: the frequency of fractures and other injuries on the side of the musculoskeletal system was significantly higher in the anastrozole group compared with the tamoxifen group. The frequency of spine fractures increased the most; there was no change in the frequency of spine fractures. Other non-specific side effects, cramps, fibrous changes and other pathological conditions of the endometrium, were more likely to occur with the use of anastrozole. The level of weight gain was similar in all three treatment groups and reached an average of 1.65 kg, or 2.5% for 2 stages in the skin group. Due to contralateral breast cancer and endometrial cancer, there was no difference in the incidence of new primary cancers between groups (Table 6).

Most patients tolerated all three treatment regimens well (Table 7). Significantly fewer types of treatment were obtained with stagnant anastrozole, when added to tamoxifen (odds ratio 0.80 [0.71–0.90], p = 0.0002), including those in Treatment for side effects (0.68 [0.57–0.81], p<0.0001).

Negotiated

Endocrine treatment of breast cancer has experienced a revival since the introduction of tamoxifen in the 70s. In fact, we can conclude that in patients before and after menopause with a positive hormonal receptor status, treatment with tamoxifen for 5 days leads to a reduction in relapse rate by 47% and overall mortality by 26%.

Table 5. Frequency of historically significant side effects

A - anastrozole; T - tamoxifen; NZ - did not work; LE - legen embolism. *On tamoxifen. f3a in patients with a history of hysterectomy at the time of investigation, the sign had numbers 2228, 2237 and 2240, consistent with anastrozole, tamoxifen and combination therapy. Endometrial cancer was detected before the disease relapsed. Three relapses (1 for anastrozole and 2 for tamoxifen) began after treatment, but before relapse was detected. In addition, 2 types of uterine cancer of non-endometrial origin were identified (type 1.0, 1) and 3 types of vulvar cancer (type 1, 0, 2). It is unknown whether the patients discontinued treatment in the hours between the initial treatment and the detected relapse. We provide figures for different localizations of fractures.

Table 6. New primary cancer tumors with a frequency of over 0.2% before relapse was detected in all patients who were treated after treatment.

The incidence of contralateral breast cancer and endometrial cancer is not included in this table, but is shown similarly in Tables 2 and 5.

Table 7. All side effects

Patients could be included in more than one category. “Before them, they covered effects that could lead to death, required hospitalization, caused disability or the need for medical care to prevent permanent injuries or disability.

Regardless of apparently good tolerability, about 30% of women experience hot flashes, pain and bleeding from the skin when taking tamoxifen. In the long term, the risk of endometrial cancer and thromboembolic complications is more serious. For these reasons, and looking at the potential for greater effectiveness, we began to investigate anastrozole, a drug that can be used instead of tamoxifen to reduce the power of a partial agonist. A group of combined treatments was also formed based on the theoretical possibility of a combined or synergistic effect of two endocrine drugs with different mechanisms of action.

The scale of the ATAS investigation and the high speed of patient recruitment led to the fact that the previously determined number of steps required for the beginning of a formal analysis could be reached at the moment when the participants in the investigation were completely finished. juvane likuvannya in the middle lichen for half an hour, designated by the protocol (totally 2, 5 roku). Almost 43% of patients underwent treatment for 2–3 days and 30% for 3–4 years. Thus, with further caution, it will be possible to obtain additional information regarding the frequency of distant metastasis and survival.

In the first analysis, anastrozole demonstrated greater effectiveness than tamoxifen (relapse-free survival rate was consistently 89.4 and 87.4% after 3 days). In addition, there was a reduction in the overall risk of relapse rate by 17% and an increase in effectiveness equal to that of the combined treatment group by 19%. The delay in time before recurrence (associated with breast cancer) resulted in a large difference in the aqueous rhizome (21 and 25% similar to anastrozole and tamoxifen). The result was even more pronounced in the subgroup of patients with a positive status of hormonal receptors, with a decrease in the apparent risk of relapse for anastrozole compared with tamoxifen to 27%. However, anastrozole is not as effective as tamoxifen in patients with negative hormone receptor status.

It is important to note that before analyzing the effectiveness of treatment with tamoxifen, the results of this study are important. The recurrence rate with tamoxifen treatment was virtually identical to the 3.5% river recurrence rate in the 1998 EBCTCG analysis after adjusting for lymph node status. This advantage of anastrozole can be explained by the greater effectiveness of the drug, and not by the suboptimal results of tamoxifen administration.

The effectiveness of the combination therapy was equivalent to tamoxifen and much worse than anastrozole monotherapy. The lesser effectiveness of the combination regimen can be explained by pharmacokinetics. Despite the fact that the concentration of anastrozole was 27% lower in the combined treatment group, the decrease in estradiol levels was similar in both groups, suggesting that this explanation is of little relevance. The combination of anastrozole with tamoxifen has a significant impact on the concentration of tamoxifen and its main metabolites.

However, pharmacological processes could be one of the reasons why anastrozole is less effective than tamoxifen and a combination regimen. Due to the presence of estrogen in menopausal concentrations, tamoxifen sits on estrogen receptors and acts primarily as an estrogen antagonist. However, since tamoxifen is a partial agonist, it produces a strong estrogen-like influx on the receptor, which limits the stage of antagonism. On the contrary, a sharp depletion of estrogen in the body when taking anastrozole can lead to almost complete blockade of the estrogen signaling system and, apparently, the same effectiveness as with tamoxifen. The association of tamoxifen with estrogen receptors and its minimal estrogen-like influx is likely not to be affected by the reduction in estradiol when anastrozole is added to the combination. Thus, the effectiveness of tamoxifen and the combined regimen will remain the same. Other potential mechanistic explanations may include the possible development of different mechanisms of resistance to tamoxifen and anastrozole at the molecular level.

When combined with tamoxifen, anastrozole resulted in a 37% reduction in the incidence of contralateral breast cancer. Monotherapy with tamoxifen led to a significant decrease in the indicator, equal to that of the control group in the first study in 1985. A later study of prophylactic use of tamoxifen showed a significant reduction in the incidence of breast cancer in high-risk women by 38% (unpublished). dani). If this tendency is preserved, anastrozole can kill (and increase) up to 80% of breast cancers with a positive status of hormonal receptors. As a result, we plan to include anastrozole in the IBIS-II protocol of another prevention study.

Another important characteristic, especially in adjuvant treatment, where the drug stagnates for three hours, is the profile of side effects of the drug. In studies of drug administration with extensive use of anastrozole, there was a significantly lower incidence of thromboembolic events compared with tamoxifen administration, as well as fewer episodes of bleeding from the epithelium. Anastrozole tablets are more often the cause of arthralgia and other pathologies of the joints when combined with tamoxifen. The lower frequency of epidermal bleeding may be due to the presence of the stimulating influx of anastrozole on the endometrium.

Data on the treatment of the main illness and the frequency of thromboembolism, urinary hemorrhage and arthralgia were confirmed in this study during trival use of drugs. Amid significant side effects, treatment with anastrozole, when combined with tamoxifen therapy, resulted in significantly fewer hot flashes, swelling and bleeding from the epithelium, and endometrial cancer. , stroke and thromboembolic conditions (including thrombophlebitis and deep vein thromboembolism).

Despite the fact that endometrial cancer is rarely seen, its association with tamoxifen treatment means that most women with gynecological symptoms will end up taking tamoxifen invasively and expensively. and quilting methods. A decrease in the incidence of illness for endometrial cancer in patients who took anastrozole (approximately equal to the same in the global population of women of the thyroid cancer group), may reduce anxiety and anxiety in women during the third hour of all costs for additional quilting. A report about this nutrition will be announced later.

In the ATAS study, women in the anastrozole group were more likely to have problems with the side of the musculoskeletal system, compared with patients who were treated with tamoxifen. The dominant problem among these was non-emergent polyarthralgia, which is likely a specific side effect of this class of drugs. There was evidence of a higher incidence of rheumatic symptoms after treatment for breast cancer and with aromatase inhibitors, as well as after postpartum and menopause, which suggests the role of hormones in the development of rheumatic diseases. stealing

A serious problem is the high incidence of fractures in the anastrozole group. Until the end of the day, this difference in the incidence of fractures may be similar to the non-treated population; however, it is lost due to the fact that it is associated with a sharp decrease in the level of estrogen. This assumption is additionally included in the framework of the protocol, which is a prospective study of mineral metabolism in the bones of the sample population of the main ATAS study. It is necessary to further understand the possibility of treating cystic disorders with the help of bisphosphonates, which can also change the risk of metastasis to the cysts.

Varto identifies two other consequences of chronic estrogen defects: disruption of lipid metabolism and cognitive function. The infusion of aromatase inhibitors on the metabolism of lipids and, as a result, the risk of ischemic heart disease is eliminated. Data from the use of anastrozole for the treatment of metastatic breast cancer do not indicate any significant effect on important indicators of lipid metabolism. In order to remove the evidence from this diet, it is necessary to pay close attention to the results of the ATAS investigation. The results of other published studies of HRT infusion on cognitive function in healthy women are superb. There is also no consistent data, but this problem is the subject of ongoing investigation.

The results of anastrozole administration in the studied ATAS are consistent only with the first identified patients with early operable breast cancer after the initial treatment (surgery, chemotherapy or combined treatment Nya). The study participants did not experience consistent treatment with anastrozole after adjuvant treatment with tamoxifen. Thus, this data cannot be used to recommend that patients who have already started taking tamoxifen be transferred to anastrozole treatment. Nutrition of post-treatment is the subject of other clinical studies.

The results of the first analysis of data from the ATAS study are encouraging, and they may be as important for the treatment of breast cancer as the results of tamoxifen treatment 20 years ago. No important nutrition is needed to treat patients as early as possible. A comprehensive assessment of the advantages and disadvantages based on clear evidence of the effects of anastrozole in the adjuvant treatment of early stages of breast cancer in menopausal women, which means that taking adjuvant endocrine therapy for menopausal women with hormone-sensitive swellings.

Prepared by Roman Shiyan

Pharmacodynamics and pharmacokinetics

Tamoxifen is a nonsteroidal antitumor antiestrogenic drug characterized by the ability to competitively inhibit peripheral estrogen receptors in target organs and tumors arising from them.

As a result, a “tamoxifen receptor-transfer cofactor” complex is formed, which, translocating into the cell nucleus , prevents the hypertrophy of cells dependent on estrogen regulation.

Sports Wiki states that the substance was first synthesized in 1971 and became the first anti-estrogenic agent among members of the class of selective estrogen receptor modulators (SREs).

It has an antigonadotropic effect and suppresses the formation of prostaglandins in tumor tissue , slows down the development of the tumor process, which is stimulated by estrogens .

After taking a single dose of the drug, the ability to block estrogens lasts for several weeks.

Promotes the release of pituitary gonadotropic hormones , thereby causing ovulation in women in its absence. With oligospermia in men, it increases the serum concentration of estrogens , testosterone , luteotropin and follitropin .

Tamoxifen and some of its metabolites exhibit the properties of powerful inhibitors (oxidases) with mixed functions (monooxygenases) of the liver cytochrome P450 system. However, how clinically significant these effects are is not known.

In some cases, Tamoxifen is effective for estrogen-independent tumors . The substance has a partial estrogen-like effect on the lipid spectrum of blood plasma , endometrium and bone tissue .

Absorption of Tamoxifen is high, TCmax is from 4 to 7 hours after oral administration of the tablet. Steady-state plasma concentrations are observed 4 weeks after the start of treatment using a dosage of 40 mg/day.

The substance binds 99% to blood plasma albumin Metabolization occurs in the liver by demethylation, hydroxylation and conjugation and with the participation of the CYP2C9 isoenzyme.

Metabolites are excreted mainly with the contents of the intestine and partly by the kidneys (insignificant amounts). Removal is carried out in two stages. The initial half-life of the main metabolite circulating in the systemic circulation ranges from 7 to 14 hours, the final slow half-life is 7 days.

Analogs

Level 4 ATX code matches:
Nolvadex

Fareston

Vero-Tamoxifen

Structural analogues of Tamoxifen: Vero-Tamoxifen , Tamoxifen Hexal , Tamoxifen Lachema , Tamoxifen-Ferein , Tamoxifen-Ebewe .

Faslodex and Fareston have a similar mechanism of action .

Fareston or Tamoxifen - which is more effective?

Fareston is an antitumor antiestrogenic non-steroidal drug based on the substance toremifene . Main features of the medicine:

• the presence of a chlorine atom in its chemical structure (which makes the drug more stable compared to Tamoxifen);
• lack of oncogenic effect ;
• ability to induce apoptosis;
• effectiveness in ER-negative tumors .

According to clinical observations conducted over six months, it was found that when taking Fareston:

• changes in hormonal homeostasis are an order of magnitude more favorable than when taking Tamoxifen;
• changes that are less dangerous for the patient in terms of cancer risk develop;
• Undesirable side effects occur an order of magnitude less frequently.

The studies also led to the conclusion that, as part of a complex treatment, the effect of Fareston on the tumor process in progressive breast cancer is more effective than the effect of its analogue: with its use, patients experienced complete remission much more often, and disease progression began at 1.2 a month later.

In addition, the antitumor effect during treatment with Fareston was observed in a larger number of patients.

Specialist consultation

To get a positive effect from taking tamoxifen for gynecomastia in men, it is better to consult an endocrinologist who will work with the patient individually, will be able to collect anamnesis, help determine the dosage, explain which drugs can be combined with and which cannot, and information received from a specialist will be much more useful than reviews of the drug on the Internet and from friends.

I, Romanov Georgy Nikitich, provide paid online consultation services. More than twenty years ago I received a higher medical education and became a practicing endocrinologist. Today I am a candidate of medical sciences, I see patients in my clinic and conduct consultations online. Over the years of work, I have gained enormous experience and helped many of my patients return to normal life.

You can sign up for my consultation in any of the presented messengers: Viber, Telegram, Instagram, WhatsApp, Skype, Vkontakte.

Drug interactions

Tamoxifen in bodybuilding is taken in compliance with the rules of drug interactions with other drugs and anabolic steroids.

When taking the drug, the following pharmacological properties of tamoxifen citrate must be taken into account:

• Tamoxifen reduces the effect of other medications that contain sex hormones of the estradiol group;
• the medication enhances the pharmacological effect of drugs that are classified as coumarin anticoagulants;
• simultaneous therapy with Tamoxifen and drugs that are platelet aggregation inhibitors increases the risk of internal bleeding;
• co-administration of Tegafur may cause progressive hepatitis or cirrhosis of the liver;
• therapy with Allopurinol increases the risk of developing hepatotoxic reactions;
• the active components of cytotoxic drugs can enter into chemical reactions with tamoxifen citrate and cause thromboembolic complications;
• simultaneous administration of Bromocriptine enhances the anti-estrogenic effect of Tamoxifen, and also increases the concentration of its metabolites in the blood serum.

Food items included in a bodybuilder’s daily diet do not affect the absorption process of tamoxifen citrate and do not change the pharmacokinetic properties of the drug.