Breast cancer drug prevention
The anti-estrogenic properties of tamoxifen became known in the 1960s; its ability to prevent hormone-responsive 7,12-dimethylbenzene (DMBA)-induced tumorigenesis in rodents was discovered in the 1970s, and its ability to clinically slow down the local development and metastasis of breast cancer led to the investigation of whether tamoxifen could prevent hormone-related tumors. The results of this study provide conclusive evidence that tamoxifen does reduce the incidence of contralateral breast cancer, making tamoxifen a logical preventive drug for breast cancer.
Tamoxifen
In 1998, the results of three randomized controlled trials (Italy, UK, USA) of chemopreventive treatment with tamoxifen (20 mg/day) compared to placebo were published: two European trials showed no protective effect of tamoxifen, while the US trial showed a significant preventive effect of tamoxifen, reducing the incidence of invasive and non-invasive breast cancer by 49% and 50%, respectively. The Italian trial was conducted only in breast cancer.
The Italian trial was conducted only in people with a lower than normal risk of breast cancer. All women had undergone hysterectomy, 48% of whom also underwent oophorectomy and 14% of whom received hormone replacement therapy (HRT). The loss to follow-up rate for the entire trial was 26%.
Of the UK trial participants with a family history of breast cancer, i.e., those at high risk of developing breast cancer, 26% received HRT during the course of the trial and 35% ended the trial early.
In the U.S. trial (National Breast and Bowel Cancer Prevention Program P1, NSABP-P1), HRT was not allowed; the trial was conducted in a population with a higher than average risk of developing cancer: 1) older than 60 years of age 2) with a history of lobular carcinoma in situ or a 5-year expected risk of developing breast cancer based on the Gail model of at least 1.66. The NSABP-P1 study included 13388 women, while in the The sample size of the observed subjects in the Italian and UK trials was much lower.
The results of these three inconsistent trials have generated robust, speculative controversy and discussion, and none of the parties to the debate has been successful because of the inconsistent trial design and the large number of confounding variables involved in the studies. However, the results of this study were recently published in the UK at 20-year follow-up, and the data showed that tamoxifen reduced the occurrence of estrogen receptor-positive (ER+) solid tumors by 39%, a result not found in the 1998 report.
The International Breast Cancer Intervention Study (IBIS-1) recruited 7,152 women with a family history of breast cancer for a 5-year maintenance study of tamoxifen. Its results confirmed the findings of NSABP-P1, showing a 32% reduction in ER+ breast cancer occurrence and no change in ER- (negative) breast cancer occurrence. However, the tamoxifen group had a 2.5-fold increase in venous thrombosis and a 21% increase in gynecologic symptoms and abnormal vasodilatory function.
The results of the 96-month follow-up in 2007 further confirmed and reinforced this effect of tamoxifen and showed that the effect of tamoxifen in reducing the incidence of estrogen receptor-positive breast cancer persists for at least 10 years. Venous thrombosis, gynecological symptoms, and vasodilatory abnormalities do not persist after a 5-year treatment period. Thus, tamoxifen reduces breast cancer incidence more significantly over time, suggesting a long-term preventive effect rather than a transient reduction in breast cancer incidence.
Tamoxifen appears to reduce the risk of contralateral breast cancer in carriers of the BRCA1 and BRCA2 variants of the gene. As a primary prevention agent, evidence suggests that tamoxifen reduces the incidence of breast cancer in BRCA2 carriers by 62%, while it does not appear to show a risk reduction in healthy carriers of BRCA1.
Raloxifene
Meanwhile, the second-generation selective estrogen receptor modulator (SERM) raloxifene underwent a randomized controlled study that was originally designed to examine whether it could reduce the incidence of fractures in postmenopausal women with osteoporosis. The results showed that four years of raloxifene treatment reduced the incidence of ER+ breast cancer by 72%, in addition to a 30% reduction in vertebral fractures. A study of women who voluntarily received raloxifene for more than four years showed a 66% reduction in the incidence of invasive breast cancer. Despite the increased thrombosis in the raloxifene group (RR=3.1), the risk of endometrial carcinogenesis in a small number of women was not found with extended raloxifene treatment.
Tamoxifen versus raloxifene as chemopreventive agents
A direct comparison between tamoxifen and raloxifene is necessary and was studied by NSABP (STAR trial) and the results were published in 2006. the STAR trial documented the incidence of invasive and non-invasive breast cancer, thrombosis, fracture, and uterine cancer in women older than 35 years at high risk of breast cancer who were treated using The Gail risk model analysis predicted a 5-year risk of breast cancer greater than or equal to 1.66. 19747 women were randomized to the tamoxifen group (20 mg/day) and the raloxifene group (60 mg/day) for 5 years. The results showed that there was no statistical difference in the data on the incidence of non-invasive breast, uterine and other cancers between the two groups; there was also no difference in the incidence of ischemic heart disease and fracture between the two groups; the incidence of typical and atypical uterine hyperplasia was significantly lower in the raloxifene group than in the tamoxifen group, as well as the incidence of deep vein embolism, pulmonary embolism and cataract; the incidence of non-invasive cancers was lower in the tamoxifen group, with an incidence The incidence of non-invasive cancer was lower in the tamoxifen group, with an incidence rate of 1.51/1000 compared to 2.11/1000 in the raloxifene group, but the difference between these two groups was not statistically significant.
Ongoing studies
The ATAC study (anastrozole, tamoxifen, or a combination of both) compares tamoxifen with an aromatase inhibitor (AI) and provides information on the value of both in preventing the development of contralateral breast cancer. The low incidence of side effects makes aromatase inhibitors very attractive as a primary chemopreventive agent. There are also several ongoing clinical trial studies comparing the preventive effects of raloxifene with AI and AI with placebo in populations at high risk for breast cancer development.
Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) and statins may reduce the incidence of breast cancer; however, no rigorous randomized controlled studies have been concluded.
In the long term, the long-lasting and stable effects of SERMs for breast cancer prevention and the decrease in side effects over time (probably due to the reduced dose of tamoxifen versus raloxifene use and the thromboprophylactic effect of low-dose aspirin) make them readily acceptable to women, preventive physicians, and oncologists.
Screening for breast cancer
Mammography as breast cancer screening
Recommendations for primary prevention continue to be discussed and are not yet routinely used in clinical practice, whereas mammography has been widely accepted as an early screening tool for many years, despite controversy.
The aim of screening is to reduce disease mortality, and therefore studies have been conducted for many years. In the past 25 years, public awareness of breast cancer diagnosis and treatment has increased, so that breast cancer mortality has been reduced with or without screening, and it is difficult to evaluate in isolation how much screening contributes to survival, and there is no evidence that breast self-examination reduces breast cancer mortality.
For a screening program to be successful in achieving its purpose, it requires high compliance (>70%), high quality radiographs and descriptions of radiographs, and precision of image-guided tissue biopsy. It is clear that the establishment of a breast cancer diagnosis alone cannot change its mortality rate, but also requires good treatment. Therefore, some screening programs have their own endpoints, not diagnosis, but completion of initial treatment.
Randomized controlled studies of mammography
Seven published, influential studies have concluded that regular mammography screening of populations significantly reduces breast cancer mortality.
And based on this finding, a number of regional and national breast cancer screening programs have emerged.
A systematic review of breast screening studies conducted in 2002 was re-evaluated in 2006 and offered many criticisms of previous studies that
n the lack of a rigorous randomized controlled design
Unclear cause of death in many cases and bias in favor of the breast cancer screening group
the presumed increased risk of cardiovascular mortality due to radiation and the higher intake of radiation in the screening mammography group compared to the control group
The review concluded that the ‘sufficiently randomized’ studies described above did not show a survival advantage in the screening group, and that the studies that concluded that screening resulted in a 25% survival advantage at 13 years were not optimally randomized. Nevertheless, the review concluded that: screening adds an unnecessary diagnostic process; screening identifies many slow-growing tumors that may never be biologically dangerous; and screening causes many cases of ductal carcinoma in situ (DCIS) to be identified that may never develop into invasive cancer. This 2002 review sparked great controversy in the scientific, medical, and even review groups.
Another meta-analysis of long-term outcomes of population-based mammography screening showed that screening reduced mortality by 22% in women aged >50 years with breast cancer. Overall, fluoroscopic screening is accepted for reducing breast cancer mortality. However, the upper age limit for screening women, and the ideal cost/effectiveness interval, are uncertain. Breast cancer incidence increases with age, and compliance with screening also appears to increase with age.
Mammography screening in women aged 40-50 years
For many years, screening mammography in women aged 40-50 years has been controversial due to the radiation density of younger women’s breasts, however, meta-analysis results confirmed a 15% reduction in breast cancer mortality with screening in these populations. Other studies, while confirming that screening reduces breast cancer mortality in women aged 40-49 years, have noted that mammography screening has a high rate of false positives (20-50%), leading to anxiety and concern in many patients who are later confirmed not to have breast cancer. For women in this age group, the risks of population-based screening may outweigh its advantages.
There is no doubt that by focusing enough on teamwork at each stage and improving quality, mammography screening programs can help improve the standard of care for all women with breast disease in the screening program, as well as outside the program.
MRI Screening for Breast Cancer
Magnetic resonance imaging (MRI) is currently being evaluated for screening in populations with a high incidence of breast cancer, and MRI appears to have a 95% specificity. In BRCA carriers, MRI detects twice as many cancers as mammography, although some cancers are detected by mammography but not by MRI. Currently, MRI and mammography can be used as complementary screening methods for women carrying the BRCA1 gene mutation and for BRCA2 carriers with radiologically dense breasts.