The normal metabolism of mammary gland is resistant to the coordinated effects of various hormones, especially estrogen and progesterone. These hormone receptors must bind to specific proteins in the cell before they can function, and these specific proteins are called estrogen receptors (ER) and progesterone receptors (PR). When cells become cancerous, the cells can partially or fully retain the normal estrogen and progesterone receptor systems, and the function of hormone receptors in tumor cells is similar to that of normal cells, indicating that the growth of the tumor cells still depends on the original hormonal environment regulation, which is called hormone-dependent tumors, accounting for about 55% to 65% of breast cancers;
On the contrary, in some tumors, the receptor system is completely lost in the process of cancer, which can no longer serve as the target cells of hormones, and its growth is no longer controlled and regulated by hormones, which is a non-hormone-dependent tumor. Accordingly, breast cancer is clinically classified into hormone receptor positive and hormone receptor negative tumors, and hormone receptor positive tumors receive endocrine therapy while hormone receptor negative tumors can only be treated with chemotherapy; one high expression of ER or PR is positive.
The following are common misconceptions in the clinical application of endocrine therapy for breast cancer.
1. If a breast cancer patient is hormone receptor positive, does endocrine therapy work well?
Endocrine therapy for breast cancer is based on the combination of clinical information of patients and the expression status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER-2) in their tumor tissues to formulate the corresponding treatment plan and predict the therapeutic effect and assess the prognosis, therefore, the ER, PR and HER-2 test results of breast cancer patients are the basis for deciding how to choose the treatment plan. Therefore, the ER, PR and HER-2 test results of breast cancer patients are the basis for the selection of treatment plan, and the test results are influenced by many factors, including the pre-treatment of specimens, fixation, test methods and laboratory quality control, interpretation of test results and standardization of pathology reports.
The prerequisite of endocrine therapy for breast cancer patients is that the ER or PR must be positive, but ER and PR positive results are a large category, ER and PR positive means that 1 positive to 90 positive receptor expressions are called positive, and their efficacy can vary greatly. Currently, there is no standard to quantify the hormone expression status, some hospitals use weak positive, positive or strong positive to express it, but most hospitals only use positive to express it, because the effect of endocrine treatment for breast cancer is also related to age, whether or not chemotherapy is given, and whether or not there is obesity. Like all information in medical oncology, the treatment effect will not be 100%, even for patients with strong positive ER and PR, the effective rate is only about 75%, and the duration of treatment effect also varies individually. Therefore, even breast cancer patients with positive hormone receptors should undergo regular medical checkups at hospitals during endocrine therapy.
2.For breast cancer patients, will hormone receptor positive expression never change and will endocrine therapy always be effective?
Currently, the only choice of endocrine therapy for breast cancer is based on the positive expression of ER and PR receptors in breast cancer tissue, which is usually selected based on the parameters at the time of primary tumor diagnosis, even for patients with metastatic cancer occurring several years later. Several studies at home and abroad have already found that the lack of concordance of tumor biomarkers between the primary tumor and metastatic site diagnosed at the same time, and the biological behavior of the tumor after therapeutic intervention can also appear or be lost, as shown by the fact that the original hormone receptor positive and effective for endocrine therapy, after chemotherapy or endocrine therapy, the hormone receptor expression is negative and endocrine therapy loses its effect;
Or the original hormone receptor negative, after chemotherapy, the hormone receptor expression is positive, and can receive endocrine therapy. The expression of hormone receptors and HER-2 in breast cancer patients will change with time and treatment. Patients with recurrence or metastasis need to obtain tissue specimens again to test for these biomarkers. If it is difficult to obtain tissue specimens, it is necessary to closely observe the changes in the treatment and change the treatment plan once the treatment effect is not satisfactory.
3.What are the adverse effects of endocrine therapy for breast cancer?
With the introduction and improvement of endocrine therapy drugs year by year, the strategy of breast cancer endocrine therapy is undergoing profound changes. With the successful development of the third generation aromatase inhibitors, its therapeutic status for breast cancer is becoming more and more obvious and gradually becomes an important means of breast cancer endocrine therapy. However, all drugs are double-edged swords and can have adverse effects while treating tumors, and endocrine therapy for breast cancer is no exception.
Tamoxifen, the first estrogen receptor antagonist introduced into clinical treatment in 1971, is regarded as a milestone in endocrine treatment of breast cancer. The mechanism of action of tamoxifen is complex, exhibiting an anti-estrogenic effect on the breast and a partial estrogen-like effect on the bone. In postmenopausal patients, because of its mild estrogen-like effects, it may prevent the progression of osteoporosis, while in premenopausal patients it may accelerate the loss of bone components. In addition, serious side effects of tamoxifen include endometrial cancer, thromboembolism, and the occurrence of cerebrovascular events.
The main adverse effects of tamoxifen are the decrease in estrogen levels and the possible development of menopause-related adverse effects, such as flushing, night sweats, rash, malaise, and in rare cases, endometrial thickening and endometrial cancer. Tamoxifen is a selective estrogen receptor modulator or inhibitor, its function in the breast part is to inhibit, but it is a stimulating effect on the endometrium, therefore, probably less than 1% of patients will develop endometrial thickening and the tendency of endometrial cancer in the distant future, so regular checkups should be done. If there is significant endometrial thickening or heavy bleeding and ultrasound test shows very thick endometrium, diagnostic scraping can be considered.
However, we also need to talk to the obstetrician and gynecologist, the chance of endometrial cancer is relatively small, so generally there is no need to worry too much about endometrial thickening, it should not be a big problem within two centimeters.
Third-generation aromatase inhibitors, a class of drugs including letrozole, anastrozole and exemestane, are mainly indicated for postmenopausal breast cancer patients. Third generation aromatase inhibitors can effectively inhibit 95-98% of aromatase activity, blocking the conversion of androstenedione and testosterone to estrogen via aromatization in tissues other than the ovaries, thus causing a significant reduction in estradiol levels, which inevitably has a complex effect on bone physiological processes in postmenopausal breast cancer patients, that is, leading to a decrease in the activity of osteoblasts and a relative increase in the function of osteoclasts, resulting in a decrease in bone mass The main manifestation of the disease is pain in the bones and joints, which can affect sleep. Elevated blood lipids may also occur.
There are several studies on the decrease in bone health due to third-generation aromatase inhibitors, and the conclusions are consistent. Therefore, it is recommended that for patients treated with third-generation aromatase inhibitors for osteoporosis prevention and treatment, the general preventive treatment is: 1. 1500 mg/d of oral calcium and 400-800 IU/d of vitamin D. 2. It is recommended to increase exercise, such as walking at least 4 times a week for at least 40 minutes each time.
4. Before and after menopause, why is endocrine therapy for breast cancer related to menopause?
In hormone-dependent breast cancer, tamoxifen is a very classical treatment drug before menopause; while for post-menopausal patients, there is a class of drugs called aromatase inhibitors. Several large clinical studies have shown that aromatase inhibitors are more effective than tamoxifen. Therefore, for premenopausal patients, tamoxifen is the main drug; for early postmenopausal patients with estrogen receptor-positive breast cancer, the current classical regimen is based on aromatase inhibitors. The level of estrogen in the body is related to menopause or not. In postmenopausal patients, the ovaries have atrophied and lost their specific functions. At this time, peripheral fat, liver and bones produce large amounts of androgens, which are converted into estrogen by aromatase. If the patient is particularly fat, the estrogen level in the body is relatively high. If the pathway from androgen to estrogen is blocked, the estrogen level will be indirectly reduced, so postmenopausal patients are treated with aromatase inhibitors, which is its mechanism.
5.How is the treatment for premenopausal patients?
Premenopausal patients are mainly treated with tamoxifen, but some high-risk and advanced patients can be artificially converted to postmenopausal status. For example, some drugs can block the release of estrogen for life, causing the estrogen level in the body to drop. By monitoring the peripheral estrogen level to determine whether she is post-menopausal or not, the patient may benefit more from the combination of tamoxifen and aromatase inhibitors as an indirect judgment based on whether she is having a “period” or not.
6. The doctor suggested her to remove her ovaries, she thought it was unbelievable.
Oophorectomy is usually done for premenopausal patients because the ovaries are still functioning very well in young patients and her estrogen level is relatively high, but the doctor must lower the estrogen level. However, ovariectomy is basically used in premenopausal patients with advanced breast cancer who are estrogen receptor positive, and this group of people can suppress their ovarian function if they do not have fertility requirements.
There are several ways to suppress ovarian function, one is to use drugs, the second is oophorectomy, and the third is radiotherapy. Theoretically, oophorectomy is the most fundamental method.
Some patients may have bone metastases, and they are relatively young and have a rapid progression of the disease, so these patients will have their ovaries removed and become postmenopausal, so that the estrogen level can be lowered.
7.Will endocrine therapy for breast cancer cause abnormal menstruation in patients?
Theoretically, it is possible, because after moxifen, the hormone level of premenopausal patients may drop, which may affect her menstrual cycle, sometimes she may not have her period, sometimes she may have menstrual disorder, sometimes she may have abnormal bleeding. But none of these will affect the general outcome of treatment, so it is a matter of side details. If the bleeding is relatively large and causes the patient to be anemic and weak, we will consider whether to stop giving the drug.
8. There are quite a number of breast cancer patients who are relatively young and have never had children and have the requirement to have children, can such patients receive endocrine therapy?
It is not recommended for advanced patients to have children anymore because the risk of survival is very high.
For early stage breast cancer patients, clinically, there are two parts: before 40 years old and after 40 years old. the suppression of ovarian function is very obvious after endocrine therapy for patients over 40 years old, and fewer people can really restore ovarian function. Therefore, we should still consider the fertility of patients under 40 years old.
It may be particularly easy for physicians to focus on treatment and survival in the clinic, and not be particularly concerned about the details of patients’ lives and fertility issues. As physicians, we should take fertility issues into account when developing early treatment plans. One solution is to freeze the follicles in vitro in advance, so that fertility can take place at the right time or after cure. Another solution is to use LHRH (LHRH stands for Luteinizing Hormone Releasing Hormone) at the same time.
It is synthesized in the neurosecretory cells of the hypothalamus, released in the median bulge, from the end of the axoneme to the vessels of the first capillary plexus of the pituitary portal system, and when transported to the pituitary gland can act directly on the luteinizing hormone (LH)-secreting cells. It has been used in recent years for the treatment of infertility.) Similarly, this drug itself has a protective effect on the ovaries, and the ovarian function recovers more quickly after the endocrine therapy is stopped, which is helpful for the patient’s future fertility. As a clinician, we must fully communicate with the patient during the treatment, whether there is a requirement for fertility and what issues should be paid attention to.
9.After the endocrine treatment of breast cancer, does it have any effect on the patient’s future children?
There is a large amount of clinical evidence abroad that there is no significant impact on the intellectual and physical development of children after endocrine therapy for breast cancer. There is some literature that the growth and development of the child is not much of a problem after 15 years of follow-up.
10. Is there any special examination for breast cancer patients who have undergone endocrine therapy after they become pregnant?
There is no special requirement. It is reported in the literature that it may be better to get pregnant more than five years after the completion of chemotherapy and radiotherapy, including endocrine therapy, but it can be considered more than two years after the completion of treatment. Of course, during this process, we must follow up and do some tests. We can do an amniotic fluid test at about three to four months to see the DNA situation and determine whether there are any genetic-related diseases.
11.When is the best time for patients to start endocrine therapy?
Endocrine therapy should be started only after chemotherapy is completed. Patients who are eligible for endocrine therapy according to the guideline can use it after surgery and chemotherapy, at least for five years. Targeted therapy and endocrine therapy can be administered at the same time.
12. About prophylactic mastectomy
Angelina Jolie, the famous American actress, chose to have a preventive mastectomy because of the mutation of BRCA1 and BRCA2 genes, which are now more researched and considered to be more related to breast and ovarian cancers, and if there is a mutation in these two genes, women are at a much higher risk of developing breast or ovarian cancer. If these women have mutations in these two genes, it should be medically feasible to have a preventive mastectomy. Many studies have been done in the United States, and preventive mastectomy can greatly reduce the mortality rate of breast cancer. However, since BRCA1 and BRCA2 genetic testing is not so popular in China, Chinese people are still relatively conservative, and preventive mastectomy is not as acceptable as in the West. Our plastic surgery, especially mammaplasty, is not as popular as abroad, which is also one of the factors that limit this approach.
As to whether we should do the BRCA genetic test, it is recommended that the general public should not do it, and it is recommended for people with high risk factors. For example, if there is a clear family history of breast cancer, if the patient has had breast cancer once and is relatively young, and if there are some special types of breast cancer such as triple negative breast cancer, these people may have a higher percentage of positive results.
13.What are the common immunohistochemical tests for breast cancer?
There are four main tests that are helpful for breast cancer treatment and healing.
1. ER estrogen receptor A positive test means that the patient is hormone receptor-dependent, which means that after surgery, endocrine therapy is more effective.
2, PR progesterone receptor Progesterone is often associated with estrogen, if there is a positive estrogen receptor and progesterone receptor positive or one of them alone, in fact, is also hormone-dependent, endocrine treatment is effective, the prognosis may be relatively good, or the development will be slower.
3, HER2 epidermal growth factor 2 receptor HER2 (also known as cerbB-2) positive is one of the indicators of poor prognosis or high malignancy, but also suggests that targeted therapy – Herceptin will be effective. HER2 is generally interpreted as negative for a plus sign, because only 5% of patients are positive and 95% are negative. 2 plus signs of positive and negative each have a part, so at this time there are conditions The hospital will recommend the patient to do a FISH test (fluorescent in situ hybridization).
If the gene is amplified, it means it is positive, and it is really positive, suggesting that its prognosis may be poor, and in addition to chemotherapy, it may also need to do targeted therapy. If the result of immunohistochemistry is 3 plus, it is generally considered positive and FISH is no longer routinely recommended.
Triple negative breast cancer means that ER/PR/HER-2 are all negative. This kind of breast cancer often means that the prognosis is very poor, such patients will recur within three to five years of treatment and often develop distant metastases quickly, thus endangering the patient’s life.
The higher the Ki-67 percentage, the more active the tumor cell growth is, and from another perspective, the higher the malignancy is. In general, it is considered to be low expression within 15% to 20% and high expression above 50%. 20% to 30% should be considered in conjunction with other conditions.
Theoretically, every breast cancer patient should have immunohistochemistry as long as it is available. For breast cancer patients, it is unfortunate to have this disease, but fortunately it has the most treatment options, and the current advanced treatments can be mastered by domestic doctors. Patients and family members must build up their confidence, only when they have built up their confidence and have a scientific understanding of the disease, the future of patients should be very bright.