QUALITY OF LIFE RELATED TO BREAST CANCER IN WOMEN IN POSTMENOPAUSE: A SYSTEMATIC REVIEW CALIDAD DE VIDA RELACIONADA CON EL CÁNCER DE MAMA EN MUJERES EN POSMENOPAUSIA: UNA REVISIÓN SISTEMÁTICA QUALIDADE DE VIDA RELACIONADA AO CÂNCER DE MAMA EM MULHERES NA PÓS- MENOPAUSA: REVISÃO SISTEMÁTICA

Objective: To verify the quality of life related to post-menopausal breast cancer in women using HT, through a systematic review. Methods: For the selection of studies, the combination [(Hormone Replacement Therapy) AND (use) AND (breast cancer) AND (menopausal women) AND (quality of life) AND (randomized controlled trial)) was used]. The search was performed in the Medline, LILACS, Bireme, SciELO, ScienceDirect and Google Scholar databases as a gray search. Randomized articles were included, without language restriction, published between January 2010 and March 2020, which obtained a minimum score of 10 on the modified scale of the literature. Articles that did not have a title, abstract or body of the article related to the research objective were excluded. Result: 1217 articles were retrieved, however two articles met the inclusion criteria, being classified as high quality. It has been observed that HT increases the risk of developing breast cancer during post-menopause. Conclusion: HT combined with different progestogens improves symptoms caused by post menopause. However, one should evaluate the advantages and disadvantages of use among women, especially when they present some risk factor for developing the disease. Lower rates of breast cancer risk were observed when HT administered with estrogen alone.


INTRODUCTION
Breast cancer is the most frequent cancer in women, impacting 2.1 million women each year, and is also responsible for the highest number of cancer-related deaths among women in the world [1] .
In Brazil, according to the José Alencar Gomes da Silva National Cancer Institute (2019), breast cancer is the most prevalent among malignant neoplasms that affect women, it is estimated that in Brazil we have about 66,280 new cases for each year of the 2020-2022 triennium, being more prevalent above 50 years of age [2] . Without considering non-melanoma skin tumors, female breast cancer occupies the first most frequent position in all Brazilian regions.
It is known that with advancing age the female body undergoes physiological changes, with perimenopause being the moment when the body begins a process of changes that precede menopause. This transition lasts an average of two to five years, depending on the individuality of each female organism [3] . Menopause is a normal and physiological event in a woman's life, characterized by the permanent suspension of menstruation and the interruption of the hormones estrogen and progesterone. Although menopause occurs naturally due to biological changes resulting from advancing 3 age, it can trigger in an artificial way, after specific clinical or surgical procedures that may lead to the stop of hormonal production [3,4] .
This life cycle of women, usually occurs between 40 and 55 years of age, the same period that according to studies, is also the most prevalent for the diagnosis of breast cancer, and accompanies a series of signs and symptoms that directly affect quality of life (QOL) [2,5] . Among the main complaints presented by women at this stage are reduced libido, menstrual irregularities, hot flushes, excessive sweating, headache, tiredness, weakness, irritability, mood changes and depression [6] .
Hormone Therapy (HT) is one of the therapies used as an ally in this process, as it helps in clinical conditions and can affect the QOL of patients [4] . However, although HT helps to attenuate some symptoms and indicate an improvement in QoL during menopause, this therapeutic method also offers some inherent risks, such as an increase in the risk indexes of myocardial infarction, strokes and breast cancer [7] .
Some studies point to HT as one of the probable causes of an increase in the incidence of breast cancer among women, however, there is still no uniformity of opinions in the scientific community [8][9][10] . According to the Brazilian Consensus on Menopause Hormone Therapy, HT is not recommended for women with a family history of cancer, since its use may trigger the onset or reappearance of the lesion [11] .
With the evident increase in the number of breast cancer cases in the female population, as well as, given the women's lack of knowledge about the effects of HT, the present study aimed to verify the quality of life of women with breast cancer during menopause or post-menopausal women undergoing hormone therapy, through a systematic review. Additionally, we sought to consider the complications and risks inherent to health when using HT.

Registration Protocol
The systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) [12] .Searches for scientific articles were conducted by two independent researchers in the electronic databases Medline (Pubmed) ScienceDirect, SciELO, LILACS and BIREME, without restrictions on location or languages, and must have been published from January 2010 to May 2020.
The research was structured and organized in the form PICOS (Table 1)  In view of these descriptors, the adequacy for the other bases used was made ScienceDirect

Inclusion and exclusion criteria
The present review included published studies that addressed the QoL of women with breast cancer in the menopause and post-menopause periods, using HT. Period included from 2010 to 2020.
There was no restriction on the language for the searches, and the included study was translated when necessary and possible.
To be admitted to the present study, publications should still score higher than 6 in the modified protocol by Pithon et al. (2015) [13] ., used to assess the methodology quality of studies.
Studies with the following characteristics were excluded: Case reports, cohort studies, screening studies, observational studies, letters to the editor, guidelines, systematic reviews, meta-analyzes and 5 abstracts. Studies that did not describe or were unclear or unavailable were also excluded. Articles published before 2010 and that scored less than six in the literature modified protocol were also excluded from the study. Table 2 represents the inclusion and exclusion criteria applied in this research. Table 2. Summary of inclusion / exclusion criteria.

Case studies and control
Intervention studies

Cohort studies
Screening studies Observational studies

Location
Without restriction

Portuguese, English and Spanish
Period January 2013 to July 2020

Exclusion Criteria
Outline Literature reviews Systematic reviews

Unclear studies
Poorly described or inadequate

Form of publication Summary only
Source: Developed by the authors.

Risk of bias
The quality of the methods used in the included studies was independently assessed by the reviewers (PH and ARF), according to the PRISMA recommendation [12] . The assessment prioritized the clear description of the information. At this point, the review was carried out blindly, masking the names of the authors and magazines, avoiding any potential bias and conflict of interest.

Data analysis
Data extraction for the studies' eligibility process was performed using a form prepared by the researchers in the Excel® 2010 Program, in which the extracted data were initially added by one of the 6 researchers and then checked by the other researcher. For the data obtained from the eligible studies, these were also transported and information was collected regarding: demographic characteristics of the patients included in the study, type of study, frequency, evaluations performed, components evaluated and results obtained.

Selection of studies
The articles admitted to this systematic review were selected by two independent authors.
Initially, the eligibility reviewer (ARF) was calibrated to perform the systematic review by AIG, KMP and PH. After calibration and clarification of doubts, the titles and abstracts were independently examined by two eligibility reviewers (ARF and PH), who were not blind to the names of the authors and the journals, those who were potentially eligible were selected and duplicate studies were excluded. Those who presented the title within the scope, but the abstracts were not available, were also obtained and analyzed in full. Articles that did not meet any inclusion criteria were excluded.
Subsequently, the preliminary eligible studies had the full text obtained and evaluated. In specific cases, when the study with potential for eligibility presented incomplete data, the authors could be contacted by email for more information, however there was no need for this research. We selected studies that presented data regarding the quality of life of women with menopausal or post-menopausal breast cancer using hormone therapy. In case of disagreement between evaluators, a third evaluator (AIG) made the decision on the eligibility of the study in question.

RESULTS
A total of 1217 articles were identified in primary searches. However, when performing the exclusion due to duplicity, 1176 articles remained, and after exclusion by title and abstracts, 52 articles

Study Description
The two studies analyzed were of the randomized controlled study type. In the study by Fahlén 10,739 women with a history of uterine cancer, with no history of breast cancer. In both studies, the type of neoplasia among the participants was not specified. Table 3 shows the indicative information for each study regarding the variables, type of study, treatment, frequency of treatment, evaluation, assessment instruments and results. However, of the 33.3% of patients who were using only tamoxifen, lower levels of anxiety and emotional function were observed when compared to those without the use of the drug. However, after one year of use, no additional benefits were seen among women who used tamoxifen, in addition to those already mentioned. On the other hand, when using HRT with estrogen and progesterone, there were numerous positive effects reported, such as the 6.8% improvement in body image and 18.2% for the sexual pleasure item, demonstrating an improvement in the overall quality of life of the woman patients [14] .
In the study by Mason et al (2013) [15] , quality of life was assessed using the RAND 36-Item Short Form Health Survey, in which it was observed that treatment with EEC associated with the use of MPA resulted in statistically significant benefits after one year after intervention in relation to physical functioning, body pain and general health, when compared to the group treated only with placebo. In addition, the group treated with isolated EEC alone was associated with a greater number of negative events in relation to emotional and social function in the scores assessed by the QOL scale.

Secondary outcomes
In the study by Manson et al (2013) [15] , the results showed that 38.7% of women in group 1a treated with HT with SCC + MPA reported feeling some mild, moderate or severe vasomotor symptom at the beginning of treatment, in the however, after five years of intervention, symptoms were reported in only 16.36% of cases. In group 2a, treated only with SCC before the intervention, vasomotor symptoms were prevalent in 43.6% and, after treatment, they were reported in only 29.15% of cases. In both groups 1a and 2a, there was an improvement in vasomotor symptoms, however, these results demonstrate a significant improvement of these symptoms in patients in group 1a, treated with conjugated estrogen plus the use of medroxyprogesterone.
Fahlén et al (2011) [14] used  [15] , was the Body Mass Index (BMI), in which 38.8% had a BMI ≥ 30, while 26.6% had a BMI <25, that is, the study sample ranged from adequate weight to grade I obesity.
As for the health risk assessment, the results of this same study [15] , showed that during the postintervention phase the results remained statistically significant, with a 1.28% relative risk of developing breast cancer in the group treated TPH with CCE + MPA , in addition to a significant relationship between the patient's age and the risk of developing the disease, when older women had higher risks when compared to younger women. However, for the group treated with estrogen alone, a reduction in the risk of developing breast cancer was observed in 0.79% of cases. It is noteworthy that, even after interrupting the use of therapy, cases of breast cancer diagnosis were reported among women in group 1a.
Another data analyzed dealt with the patients' risk of developing endometrial cancer, in which it was verified that after cessation of use, there was a 0.3% drop in the risk of developing cancer in group 1a [15] . In the study by Fahlén et al (2011) [14] , no recurrence of breast cancer was reported among women in groups 1a and 1b, using HT.

DISCUSSION
The purpose of this research was to search for and analyze scientific evidence on the effects of hormone therapy on breast cancer in menopause. The studies analyzed in this research [14,15] , showed marked vasomotor symptoms in both samples and, a significant improvement after the use of HT, included in the patients' quality of life. However, in only one of the studies [15] , it was found that even after the treatment ceased, the risks of developing breast cancer remained relatively high, in addition to the risk of developing endometrial cancer among women.
According to the Ministry of Health, among the main risk factors for developing breast cancer are age, family and personal history, lifestyle, obesity, hormonal therapy, among others [16] . In a crosssectional case-control study carried out in Bahia, the authors verified the association between body mass index and breast cancer. In this study, with 190 participants, where 70.8% of the study sample was in menopause and only 30.9% used HT. A great relationship was observed between obesity and the occurrence of breast cancer among women, indicating overweight as a risk factor for developing breast cancer [18] .
In line with this finding, in one of the studies the Body Mass Index (BMI) ≥ 30 was observed in most of the sample, 38.8% had grade I obesity, demonstrating another risk factor favorable to the occurrence of the disease [15,16] . In addition, according to the literature, women who are physically active have a lower risk of developing the disease when compared to sedentary women [18] . If we analyze the risk factors established in this study, the chances of a woman in menopause to develop breast cancer can be increased by the number of factors in this population, such as age, obesity and the use of HT.
Regarding the use of hormone therapies, Fournier, Berrino and Clavel-chapelon [19] , through a prospective cohort study, investigated the risk factors for cancer in women in the metropolitan region of France. In this study, approximately one million volunteers participated, aged between 40 and 65 years, where 70% used HT for an average period of seven years. A higher relative risk of developing the disease was observed among women who used hormonal therapy, being possible to observe it before two years of use, when compared with those women who never used the hormone. In addition, there was a significant increase in risk among women who used estrogen plus different progestogens, when compared to those who used estrogen alone.
Similar data to the study by Fournier, Berrino and Clavel-chapelon [19] were found in our review, where greater risks of developing breast cancer were found among women who used estrogen combined with different progestogens. Despite the data found in this review, it is at odds with those reported by the National Cancer Institute (INCA) [20] , where the risk of developing a disease decreases progressively after discontinuation of HT. Among the studies analyzed, disease diagnostic tests were reported after the hormone was stopped, showing that minimal exposure to hormone therapy can increase a woman's risk of developing breast cancer.
Although some authors report disagreement in the relationship between the use of HT and breast cancer [8] . In a population-based case control study carried out in the United States, with 1,044 patients aged 55 to 74 years old, they aimed to assess the relationship between the use of HT and cases of breast cancer. In this study, the authors evidenced 2.7 and 3.3 times more risks of lobular and ducto-lobular carcinoma, respectively, regardless of tumor stage, size or nodal status. In addition, the increase in risk indices was evidenced in users who used estrogen and progestogen combined for a period of three years, and no relevant evidence was found after use for longer periods [21] .
Although the studies analyzed in this review do not specify the type of cancer prevalent among the participants, the data presented by a study in the literature indicates the risks and benefits of using HT among women. Among the benefits mentioned are the decrease in the occurrence of osteoporosis and coronary heart disease, however, the risks of using this therapy include the occurrence of venous thromboembolism, especially when combined with the progestogen [22] . Therefore, the results of this study prove to be plausible that the use of hormone therapy can increase the risk of women developing breast cancer during menopause. This index may change depending on method hormone used, the woman's age and, especially, the time of hormone use, where a considerable increase in the risk of developing breast cancer in women using hormone therapy for prolonged periods is observed.

CONCLUSION
As discussed in the present study, the use of HT presents risks and benefits during menopause. As a benefit, we can mention the treatment and prevention of osteoporosis and reduction of vasomotor symptoms, directly interfering in the quality of life of women. As health risks for women, many authors point out divergences regarding the use of hormone therapy and the development of breast cancer in menopausal women, despite strong evidence regarding the risk factors for the occurrence of the disease, especially in women aged more advanced.
As for the applicability of HT in women with risk factors for the occurrence of breast cancer, the use of combined hormonal therapy is not recommended, since the rates of disease development were higher in women who had a risk factor for the disease despite this, lower rates of breast cancer risk were observed when hormone therapy was administered with estrogen alone.
The diagnosis of breast cancer is performed through detection tests such as breast self-examination, mammography with abdominal protection, which must be complemented with breast ultrasonography due to inconclusive results of the imaging exam due to the physiological changes of the breast, for a conclusive diagnosis breast biopsy in addition to MRI can also be performed.
The delay in the diagnosis of cancer and the effects of the treatment end up causing physical mutilations and changes in lifestyle. Finally, use for a period of more than five years is not indicated by scientific evidence, since in the studies analyzed, the time of use directly influenced the occurrence of the disease.