Prolonged Use of Implantable Hormonal Contraceptives Associated with Increased Risk of Breast Cancer
Hormonal contraceptive medication is a common form of preventing pregnancy for young women who are sexually active. Various forms of contraception have been created since the introduction of the birth control pill in 1960. For many women, contraception is convenient and prolong its use until pregnancy is desired. Not only do woman use contraceptive measures to prevent unwanted pregnancy, but they may also be used to regulate the proper release of hormones for regular and tolerable menorrhagia, or to clear acne. Recent research has identified a correlation between prolonged use of oral contraceptives and the risk of developing breast cancer. Implants are another form of contraception and work by releasing the hormone progestin to prevent pregnancy, typically lasting up to four years. The goal of this project is to determine the risk of breast cancer associated with prolonged use of hormonal implants inserted directly under the skin of a women’s arm or intra-uterine devices.
Specific Aim 1: To test the hypothesis that prolonged use of hormonal contraception increases the risk of developing breast cancer.
Rationale 1: Combined hormonal contraception contains the use of both synthetic estrogen and progestin, and is associated with the increasing risk of breast cancer following long-term usage. One study showed that long-term usage combined contraception with a high dosage of progestin for 4 to 5 years was associated with the increased risk of breast cancer. (7)
Specific Aim 2: To test the hypothesis that progestin-only hormonal contraceptives, such as implantable contraception devices, pose the highest risk for developing breast cancer.
Rationale 2: One study examined the level of hormonal exposure in various types of oral contraceptives to determine the relative increase in risk of developing breast cancer. Researchers concluded that contraceptives providing a significant increase in the levels of progestin hormone contribute to a considerable increase in the risk of breast cancer. (1)
Significance
Identifying the risk of developing breast cancer caused by implantable hormonal contraceptives may allow for targeted therapies for current breast cancer patients who previously used these types of contraceptives. Additionally, it may allow for revised methods of contraception that limit the amount and type of hormones released to reduce this associated risk of breast cancer. More studies are needed to examine the effects of contraceptives in genetically predisposed women, women who currently have another form of cancer, or other lifestyle measures contributing to the incidence of breast cancer not due to hormonal contraception. Research on this topic is important as the use of hormonal forms of contraception has become increasingly common among women during their reproductive years. This study intends to identify a form of implantable contraception that may contribute to the increasing prevalence of breast cancer. With this knowledge, we may be able to modify current contraceptive prescriptions to allow for safe administration and develop targeted treatments for women already diagnosed with breast cancer.
Background
Introduction
Breast cancer largely affects women during their reproductive years, with the highest prevalence of women affected between the ages of 50-64, during the menopausal or post-menopausal years. It is the most common form of cancer in women and the risk of its development increases every year until reaching menopause. There are many risks associated with the development of breast cancer including age, geographical location, genetic predisposition, lifestyle choices, and specific to this study, use of hormonal contraceptives. (2)
Types of Breast Cancer
There is a multitude of diagnostic criteria for breast cancer that occurs in unique stages ranging from stage zero to stage four of the disease (See Figure 1) (9). Diagnosis depends on the size of the cancerous tumor, whether the cancer is non-invasive or invasive, whether the cancer has spread to lymph nodes, and whether or not the cancer is metastatic. (10) The first stage, stage zero, is often referred to as ductal carcinoma in situ or lobular carcinoma in situ, which is found either in the milk ducts or lobules of the breast tissue. (3) These types of breast cancer are non-invasive, meaning that the cancerous cells have not migrated from the area in which they began to form. Stage one breast cancer falls into two categories. Stage 1A breast cancer is diagnostic of a tumor less than two centimeters not infecting the lymph nodes, while Stage 1B is diagnostic of the same size tumor with cancerous cells invading less than four lymph nodes. (3) Stage 2A breast cancer involves multiple combinations – only less than four of the lymph nodes have been affected, there is only a tumor between two and five centimeters, or there is a tumor less than two centimeters with less than four infected lymph nodes. (4) Stage 2B is more serious and indicates a tumor between 2 and 5 centimeters in addition to cancerous cells growing in less than four of the lymph nodes or only a tumor larger than 5 centimeters with no cancerous cells found in the lymph nodes. (4) Stage 3A describes more serious variations of breast cancer including either infection of more than four lymph nodes, a tumor larger than five centimeters in addition to cancerous cells found in the lymph nodes, or a tumor larger than five centimeters with infected lymph nodes of the armpit or breast wall.(5) Stage 3B breast cancer may also be referred to as inflammatory breast cancer, meaning that a cancerous tumor is present in addition to infected breast skin, chest wall, and lymph nodes. (5) The fourth and final stage of breast cancer is the most severe with the lowest survival rates, in which the cancer has infected other organs.(6) The overall five-year survival rate for those affected by breast cancer is approximately 90%, but decreases significantly depending on the stage of diagnosis. (8) Diagnosis usually occurs with the presence of an abnormal growth or through mammography, a normal screening mechanism for women between 50 and 64 years of age.
Breast Cancer Pathophysiology
Breast tissue is composed of numerous ducts leading to lobules at their terminal ends (See Figure 2) (11). Growth of breast tissue occurs during puberty and throughout pregnancy in order to increase the number and size of lobules for sufficient milk production. Receptors on breast tissue respond to hormones such as estrogen and progesterone to induce tissue proliferation. (11) Breast cancer involves the abnormal growth of cancerous cells invading the lobules or ducts of breast tissue, which may be due in part by the overstimulation of estrogen and progesterone receptors. (11) In particular, this study intends to examine the risk of breast cancer associated with prolonged use of hormonal contraceptives, which may target the receptors in breast tissue that lead to abnormal proliferation of cancerous cells.
Familial Breast Cancer
Risk of breast cancer increases with any family history of breast cancer, and probability of diagnosis increases with inherited genetic mutations. BRCA1 and BRCA2 are both tumor suppressor genes associated with a 50-80% chance of developing breast cancer. (11) Both genes function in DNA damage repair – any mutations to BRCA1 can lead to a “basal-like phenotype of breast cancer, high grade III subtype, high mitotic count, and triple negative (ER/PR/HER2) carcinomas.” (11) BRCA2 mutations are associated with “breast carcinomas that are ER and PR positive.” (11) Another gene mutation associated with the development of breast cancer occurs on the proto-oncogene known as HER2. Normal expression of this gene promotes healthy growth and repair of breast tissue, but in certain breast cancers mutations in HER2 can cause overexpression of receptors and in turn, uncontrolled growth. (12)
Current Research
Breast cancer research has identified a relationship between high-dose, prolonged usage of oral contraceptives and the prevalence of breast cancer in women. (7) Estrogen and progesterone are essential hormones naturally released during a woman’s menstrual cycle and pregnancy, suggesting that the additional hormones provided by contraceptives may lead to abnormal cell growth. Oral contraception falls into two categories – combination or progestin-only contraception. Combination contraception involves a combination of estrogen and progesterone throughout a 28-day menstrual cycle typically found in “the pill,” whereas progestin-only contraception is used in the implantable forms of contraception that will be examined in this study. Combination contraception has been widely studied to identify that the high-progesterone component is a risk factor for the development of breast cancer, but this study aims to identify that high-progestin in the implantable forms pose an even higher risk.
Long Term Goals
We predict that this study will identify that implantable hormonal contraceptives with a high-progestin component pose the highest risk for breast cancer. By pinpointing precisely which form of contraception and by which method of administration leads to the highest prevalence of breast cancer, we will be able to develop safer forms of contraception and come up with more definitive treatments. We will need to carefully screen participants for numerous covariates that may affect the results of this type of long-term study. The risk of developing breast cancer is due to several factors either alone or in conjunction with hormonal contraception, and we want to limit any false correlations drawn to the results. Risk factors for breast cancer include, but are not limited to: age, age at menses or menopause, geographical location, age contraception was begun, genetic predisposition or family history, and lifestyle choices. (2) Each factor must be taken into account carefully upon review of results to determine whether or not implantable contraception poses the highest risk in developing breast cancer. Additionally, a few problems may arise for the duration of this study. One problem being answer bias, in which women may refrain from disclosing every detail of contraceptive use. Recall bias may also pose a problem, in which women may be unable to recall an accurate timeline for past contraceptive use. Another problem may be recruiting women with terminal breast cancer, in which data collected may become inconclusive.
Experimental Approach
The experimental unit that will be examined in this study is women diagnosed at any stage of breast cancer who previously used an implantable form of hormonal contraception for at least five years, to determine if prolonged exposure to progestin contributed to the incidence of breast cancer. They will be observed in the form of a case-control study to compare with women diagnosed with breast cancer who have not used any form of contraception. Women will participate in an open-ended interview to discuss previous implantable contraceptive use and diagnosis of breast cancer. We will ask questions such as dosage of implantable contraception, duration of use, age of onset of breast cancer, etc. We do expect answer and recall bias to occur in these interviews, but generally expect valid data. Inclusion criteria for this experiment must be women of any age who have been diagnosed with breast cancer and have used a form of implantable hormonal contraception for at least five years. Exclusion criteria must be women genetically predisposed to breast cancer, women diagnosed or previously diagnosed with other forms of cancer, or women who have not previously used contraception for five years. We must include this exclusion criteria because it may affect any correlations made between the incidence of breast cancer associated with prolonged use of implantable hormonal contraception.
We aim to recruit 500 participants by use of flyers in hospital settings throughout the country detailing the purpose of the study, eligibility criteria, and contact information of researchers involved. Once participants have been recruited and have received informed consent, they will be grouped into specific age cohorts, of 125 participants each, to control for the influence of this covariate on risk of breast cancer. Participants will then be broken into groups to compare relative risk of developing breast cancer in women of each age cohort who either did or did not use implantable hormonal contraceptives for at least five years. The following table discusses each variable that will be accounted for in this study.
Variable Name
Covariate
Independent/Dependent
Continuous/Nominal/Ordinal
No previous contraceptive usage
Control
Nominal
Length of contraception usage
Independent
Continuous
Age of diagnosis
Covariate
Independent
Continuous
Age of menses
Covariate
Independent
Continuous
Age of menopause
Covariate
Independent
Continuous
Race/ethnicity
Covariate
Independent
Nominal
Smoking/alcohol history
Covariate
Independent
Nominal
Genetic predispositions
Confounder
Independent
Nominal
Stage of breast cancer
Primary outcome variable
Dependent
Nominal
The following flowchart depicts the assignment of participants to their respective experimental groups. Participants will be broken into age cohorts, as previously stated, and further broken into categories of whether or not they previously used implantable hormonal contraceptives. Examining the participants in this manner will eliminate the covariance of age associated with risk of developing breast cancer. This will allow us to determine if there is truly a risk of prolonged use of hormonal contraceptives associated with the risk of developing breast cancer.
Ethical Issues
We do not foresee any ethical issues occurring with our study. All participants will be given informed consent and the option to leave to study at any point if they please. No actual treatment will be given, a simple observational case-control study will be conducted. Patients with terminal breast cancer may participate in the study, but if the data becomes inconclusive we will detail this in a discussion section.
Statistical Approach
The statistical test that will be used to analyze our data for significance will be a two-way ANOVA. The categorical independent variables in this study are the age cohorts of women participants, which is important to account for this major covariate, and whether or not they have previously used progestin-only implantable hormonal contraceptives. The dependent variable is the incidence of breast cancer found in these groups. From the results of this statistical test, we can then determine if we have observed an increased prevalence of breast cancer in women who have used contraceptives to conclude that there is a positive correlation of prolonged use and risk of breast cancer.
Predictions and Expected Results
We expect to observe a significantly increased risk of developing breast cancer in participants who used progestin-only implantable hormonal contraceptives compared to those who did not use any form of contraception. The bar graph in Figure 3 shows the hypothetical incidence of breast cancer we expect to observe in each group, so that we may determine whether or not there is a correlation with the prolonged use of progestin-only implantable hormonal contraception. In this example, there is a clear correlation between contraceptive use and percent incidence of breast cancer. We can infer from results like these that women who use progestin-only hormonal contraceptives for at least five years have a remarkable increase in their percent risk of developing breast cancer.
Though we may be able to pinpoint this clear correlation, further studies need to be performed to eliminate all other covariates that influence the development of breast cancer. Cancer is a heavily researched disease and is unique in every individual, so it will be hard to determine conclusive information from this study alone. Ultimately, we hope to encourage revisions to current contraceptives to make it safer for women who take contraception during their reproductive years. We also hope to identify a more significant correlation between progestin-only hormonal contraception and the risk of breast cancer to allow for more specific treatments for breast cancer patients. We want women to be able to continue taking contraception in order to prevent unwanted pregnancy or for its various other uses, and not fear a risk of developing cancer later in life.
References
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