Introduction
It is currently estimated that one in eight women (12.5%) in the United States will be diagnosed with breast cancer. For example, In the year 2014 232,670 new breast cancer cases and 40,000 deaths were reported for women living in the United Sates. Age is the strongest risk factor for breast cancer. Surprisingly, breast cancer begins to rise in the third decade of life. This unusual aspect of breast cancer, is postulated to be related to the effects of ovarian hormones – especially estrogen and progesterone - on breast tissue. More than 2/3 of all new cases occur after the age of 55 and women older than 65 have a relative risk greater than 4.0 when compared with those younger than 65.
For this reason, it is imperative that causative agents responsible for the transformation of normal breast tissue cells to a cancerous state be more fully understood; that women be encouraged to undergo the appropriate screening and health checkups; and that more anti-breast cancer therapies be developed to combat this disease.
Additional Risk Factors
In addition to the endogenous ovarian hormones as cited earlier, there are the following factors that may play a significant role in the etiology of breast cancer –
- Genetic factors such as the BRCA1 and BRCA2 genetic mutations and family history of the disease pointing to genetic factors that are poorly understood.
- High levels of HER2 (HER2+) – an epidermal growth factor –can trigger uncontrolled cell division in breast tissue. TCHP is a combination drug treatment that includes docetaxel, carboplatin, trastuzumab, and pertuzumab. These are drugs that people take intravenously to kill cancer cells if they have early-stage HER2+ breast cancer.
- Reproductive history
- High dose radiation to the chest
- High dose hormone therapy
- Obesity
- Alcohol Consumption
- Environmental factors related to the abundance of carcinogenic compounds that permeate the environment.
Endogenous Estrogen Levels and the Etiology of Breast Cancer
The Data accumulated in the past few decades indicate that endogenous estrogens play a very important role in regard to the etiology of breast cancer. For this reason it is important to understand how estrogens are produced and metabolized in the body. Estrogen and Progesterone are steroid hormones, and the first step involving steroidogenesis in the human ovary is the transport of their precursor, cholesterol into the mitochondria. This is followed by a number of enzyme-mediated steps that lead to the formation of Pregnenolone that is the precursor for all steroid hormones, and eventually to estrogen.
In premenopausal women, estradiol synthesized in the ovaries is the most predominant form; whereas in postmenopausal women, estrone is the most prevalent and is synthesized in the peripheral tissue. Estrone is reversibly converted to estradiol through an enzyme-mediated reaction. Testosterone, in turn, is converted to estradiol by the action of aromatase enzyme in the peripheral tissues. Aromatase is the enzyme that mediates the rate-limiting step in the conversion of androgens like testosterone into estrogens. On account of the paramount importance of this metabolic step, pharmaceuticals that can effectively block aromatase activity have proven to be important aspect of the treatment of estrogen-dependent diseases such as breast cancer, endometriosis, and endometrial cancer.
It has been well established that active genes within the DNA serve as molecular blueprints for the production of unique proteins. The steps in chemical metabolism within all the cells in the human body are mediated by specific enzymes that act as highly specialized chemical catalysts. Enzymes are proteins. Without enzymes life on earth would not be possible. The dictum, “one gene one enzyme” can be applied universally throughout life.
It is important to keep in mind that by the very nature of their integration into DNA, genes are inheritable. It is not uncommon to find polymorphisms within genes that are slight variations in the structure of those genes and what is referred to as single nucleotide polymorphisms (SNPs) that represent a singular change in the gene. These variations in genetic structure produce corresponding variations in the proteins that are encoded in the genes that are the blueprints for these proteins.
Given this overall view, genetic research in regards to breast cancer is guided by an investigation of the genes that encode the structure of the enzymes involved in estrogen production. The driving motivation of some of this work is to find the answer to the following question – Could the polymorphisms and SNPs in the genes responsible for the production of estrogens that are found in breast cancer patients result in an over-production of estrogens? Secondly, could this over-production trigger the onset of breast cancer?
Clinical data that reinforces the primacy of estrogens in the onset of breast cancer are the following:
- Bilateral oophorectomy (ovary removal) significantly reduces breast-cancer risk, and that risk reduction is greater if the ovaries are removed earlier in life.
- In addition, some of the well-established risk factors for breast cancer, including early onset of menarche (menstruation) (<12 years), late menopause (>55 years), nulliparity or having child late in life, are related to lifetime exposure of breast tissue to sex hormones.
- Approximately 2/3 of breast tumors are estrogen receptor (ER) positive (ER+) and responsive to circulating estrogens, and that almost all ER negative (ER−) cases are resistant to endocrine therapy, it is important to elucidate the specific mechanisms by which estrogens are related to elevated breast cancer risk.
In fact, circulating primary hormones in postmenopausal women, increased circulating concentrations of estradiol, estrone, estrone-sulfate, and androstendione have been shown to correlate with higher breast cancer risk. A thorough analysis of 663 women who developed breast cancer and had not received any hormonal-based therapy, demonstrated that the risk of breast cancer significantly increased with higher endogenous levels of total estradiol, free estradiol, estrone, estrone-sulfate, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and testosterone. Since this analysis was published, a few more prospective and case-control studies have been reported that have found similar results. It should be noted that the majority of populations studied were general populations with average breast cancer risk who were not taking any exogenous sex hormones.
In addition the levels of endogenous estrogens were studied in those patients that had a number of breast cancer risk factors including obesity, reproductive, demographic, and life style factors has been investigated by the Endogenous Hormones and Breast Cancer Collaborative Group in several studies. The results of these studies did not a show a statistical significance for the association between BMI (a metric whose value can be indicative of obesity) and breast cancer risk. However, in another cross-sectional analysis of 13 prospective studies by the same group, “estrogen and androgen levels were positively associated with obesity, smoking (15+ cigarettes daily) and alcohol consumption (20+g alcohol daily), and inversely linked with age.”
Although this summary does not include any data regarding the role of the level of endogenous androgens or progesterone in regard to the onset of breast cancer, the role of estrogens in the biology of breast cancer is very significant, and has led to the development of hormonal therapy medications as a way to limit the exposure of breast tissue to circulating estrogens. What follows is a more detailed look at these therapeutic approaches.
“Hormonal therapy medicines are used in four ways: (Jenni Sheng, MDJohns Hopkins University School of Medicine, Baltimore, MD)
“If the breast cancer is large and hormone receptor-positive, your doctor may recommend hormonal therapy before surgery to shrink the cancer. Treatments given before surgery are called neoadjuvant treatments, so hormonal therapy given this way is called neoadjuvant hormonal therapy.
“To reduce recurrence risk: If you’ve been diagnosed with early-stage hormone receptor-positive breast cancer, your treatment plan will include hormonal therapy after surgery and possibly other treatments to reduce the risk of the cancer coming back (recurrence). Treatments given after surgery are called adjuvant treatments, so hormonal therapy given this way is called adjuvant hormonal therapy.
“To stop advanced-stage cancer from growing: If you’ve been diagnosed with advanced-stage, hormone receptor-positive breast cancer, hormonal therapy can be used to help stop the cancer from growing.
“To reduce the risk of a first diagnosis: Hormonal therapy also can be used to reduce breast cancer risk in certain women who haven’t been diagnosed. Women with a much higher than average risk of breast cancer may take a hormonal therapy medicine preventively to reduce the risk of hormone receptor-positive breast cancer developing.
“How does hormonal therapy treat breast cancer?
Hormonal therapy medicines work in two ways:
- by blocking estrogen production in the body
- by blocking the effects of estrogen on breast cancer cells
“Hormonal therapy is not a treatment option for hormone receptor-negative breast cancer.
“It's important to know that hormonal therapy for breast cancer is different than hormone replacement therapy (HRT) for treating symptoms of menopause. HRT isn't used to treat breast cancer. HRT is taken by some women to treat troublesome menopausal side effects such as hot flashes and mood swings. HRT is used to raise estrogen levels that drop after menopause. HRT contains estrogen and can contain progesterone and other hormones. Hormonal therapy for breast cancer is exactly the opposite — it blocks or lowers estrogen levels in the body.
“Types of hormonal therapy to treat breast cancer
“There are three main types of hormonal therapy medicines used to treat breast cancer:
• Aromatase inhibitors stop the body from making estrogen.
• Selective estrogen receptor modulators (SERMs) block the action of estrogen on certain cells.
• Selective estrogen receptor downregulators (ERDs) block the action of estrogen on certain cells.
• Aromatase inhibitors
“Aromatase inhibitors lower estrogen levels by stopping the enzyme aromatase from changing other hormones into estrogen. In estrogen receptor-positive breast cancer, the hormone estrogen can stimulate the growth of breast cancer cells.
“There are three aromatase inhibitors used to treat breast cancer:
• Arimidex (chemical name: anastrozole)
• Aromasin (chemical name: exemestane)
• Femara (chemical name: letrozole)
“Selective estrogen receptor modulators (SERMs)
“Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can’t attach to the cancer cell and the cell doesn’t receive estrogen’s signals to grow and multiply.
“There are three SERMs used to treat breast cancer:
• Tamoxifen in pill form, also called tamoxifen citrate (brand name Nolvadex), and in liquid form (brand name: Soltamox)
• Evista (chemical name: raloxifene)
• Fareston (chemical name: toremifene)
“Selective estrogen receptor downregulators (SERDs)
“Selective estrogen receptor downregulators (SERDs), much like SERMs, block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. SERDs also lower the number of estrogen receptors and change the shape of breast cell estrogen receptors so they don’t work as well. There are two SERDs used to treat breast cancer:
• Faslodex (chemical name: fulvestrant)
• Orserdu (chemical name: elacestrant)
“Hormonal therapy side effects
Each hormonal therapy medicine may cause different side effects.
The most common side effects of the aromatase inhibitors are:
• joint and bone pain
• hot flashes
• fatigue
• weakness
“The most common side effects of the SERMs are:
• hot flashes
• vaginal discharge
• mood swings
• fatigue
“The most common side effects of the SERDs are:
• nausea
• bone pain
• fatigue
• hot flashes
• injection site pain (for Faslodex only)
“For many years, women took hormonal therapy for five years after surgery for early-stage, hormone receptor-positive breast cancer. In most cases, the standard of care is five years of tamoxifen, or two to three years of tamoxifen followed by two to three years of an aromatase inhibitor, depending on menopausal status.
“Recent research has found that in certain cases, taking tamoxifen for 10 years instead of five years after surgery lowered a woman’s risk of recurrence and improved survival.
“In most cases, a post-menopausal woman diagnosed with early-stage, hormone receptor-positive breast cancer would take an aromatase inhibitor for five years after surgery to reduce the risk of recurrence. After that, if breast cancer had been found in the lymph nodes, called node-positive disease, a woman would take an aromatase inhibitor for an additional five years, for a total of 10 years of hormonal therapy treatment.
“Doctors call taking hormonal therapy for 10 years after surgery extended adjuvant hormonal therapy.
“Ovarian suppression or removal
“In pre-menopausal women, most of the estrogen in the body is made by the ovaries. In some cases, medicine may be used to stop the ovaries from functioning temporarily, called ovarian suppression or ovarian shutdown. Two medicines commonly used are:
• Zoladex (chemical name: goserelin)
• Lupron (chemical name: leuprolide)
“These medicines are given as injections once a month for several months or every few months. They can be used alone or in combination with other hormonal therapy medicines to treat pre-menopausal women.
“Once you stop receiving the medicine, your ovaries usually begin functioning again. The time it takes for the ovaries to recover varies from woman to woman.
“Some women with a much higher than average risk of breast cancer may choose to have their ovaries removed, called prophylactic or preventive ovary removal, either before or after being diagnosed with breast cancer.”
This article is designed to summarize the known relationship between estrogen levels and the majority of breast cancers (ER+). It is important to keep in mind that this area of scientific, medical and clinically-based research is constantly generating new data, and the findings presented above do not represent the last word on the understanding of this devastating illness.
