Hormones are molecules that act like chemical messengers in the human body. Their main circulating path is through the blood stream. Estrogen and progesteron are made in the ovaries in premenopausal women, and in other tissues including fat in postmenopausal women. Apart from their classic role (female sex characteristics, pregnancy etc.), they are also involved in the growth of approximately 70% of breast cancers (also known as hormone sensitive cancers). Tumor cells express certain receptors (for estrogen - ER, and progesteron - PR/Pgr) on which hormones bind, activating a cascade of reactions that alter the expression of genes, which in turn lead to cell growth(1).
To determine the hormonal status, tissue from the tumour is needed. It can be obtained either by biopsy, or by surgery. If local or distant recurrence of the disease occurs, retesting for hormonal and HER2 receptors status is recommended, because different molecular profiles are seen in up to 25% of patients, influencing the choice of treatment and prognosis(2,3).
Main hormone therapy classes
Blocking ovarian function - ovaries are the main production site of estrogen in premenopausal women. Blocking of their function can be achieved by either removing ovaries surgically, or by radiation (both being definitive methods) or, most frequently used today, inhibiting their function temporarily by using gonadotropin releasing hormone (GnRH) agonists or luteinizing hormone releasing hormone (LH-RH) agonists. Examples: goserelin and leuprolide.
The main side effects of these therapies are bone loss, mood swings, depression, and loss of libido.
Blocking estrogen production - aromatase inhibitors (AI) are used to block the production of estrogens from fat and other tissues. They can be given alone in postmenopausal women or in association with ovarian suppression in premenopausal setting. Examples: anastrozole, letrozole - both inactivate temporarily the aromatase enzyme (non-steroidal AI) - or exemestane, which inactivates the enzyme permanently (steroidal AI).
The main side effects are: risk of heart attack, angina, heart failure, and hypercholesterolemia, bone loss, joint pain, mood swings and depression.
Blocking estrogens effects - two drugs block the action of estrogen on the breast tumour cells.
Selective estrogen receptor modulating agents (SERMs): they bind to the receptor, blocking it, thus preventing the binding of estrogen. Examples: tamoxifen and toremifen. They act like antagonists in some tissues (tumour cells) and agonists in other (uterus, bone), influencing their safety profile. Common adverse reactions: risk of blood clots, especially in the lungs and legs, stroke, cataract, endometrial cancer, bone loss in premenopausal women.
Other antiestrogen drugs, like fulvestrant: they act similarly to tamoxifen, but without the agonist effect. Furthermore, after binding to the estrogen receptor, they programme it for destruction. This explains the better safety profile and side effects: gastrointestinal symptoms, elevated liver functional tests, loss of strength and pain(4-7).
Taking into account the medical history of patients and other treatments they are undergoing, we must be careful for interactions. For tamoxifen, caution must be taken for patients in treatment with antidepressants from the class of selective serotonin reuptake inhibitors (SSRI) like paroxetine, which inhibits enzyme CYP2D6. They slow down tamoxifen metabolization and reduce its effects. Caution must be taken, because approximately 25% of these patients suffer from depression and take treatment. Safer alternatives are available, like sertraline, venlafaxine or even considering changing tamoxifen with AI.
Prevention. The STAR P-2 trial showed that in women with high risk of developing invasive breast cancer, tamoxifen taken for 5 years resulted in a risk reduction with 50% for developing the disease. The same indication for AI is still under investigation(8).
Neoadjuvant. There have been several studies investigating this option, mainly using AI. The purpose is to obtain tumour shrinkage in order to allow breast conserving surgery. Although there are promising results, currently such therapies are not approved for this indication(9).
Adjuvant. Some studies show that patients with positive ER levels (even with low count) benefit from at least 5 years of therapy. Newer studies extend this period to 7 or even 10 years.
In premenopausal patients at high risk (young age, high grade tumour, lymph node involvment), aromatase inhibitor with associated ovarian suppression or tamoxifen for 5 years can be considered based on SOFT and TEXT trials results.
There are different strategies, involving either starting with tamoxifen for 2-3 years, then switching to AI or tamoxifen for 5 years and switching afterwards, or starting with AI plus ovarian suppression.
In postmenopausal patients, the standard of care is IA for at least 5 years (up to 7-10 years, according to some authors) or tamoxifen/fulvestrant if progression or intolerance. Newer options (like palbociclib) are available for ER, PGR + and HER2 patients.
Also, we must bear in mind the adverse reactions profile. For tamoxifen, the cardiovascular risk and of uterine cancer (requiring anual echographic monitoring), and for AI, mainly the risk for bone health (annual DEXA and supplements of calcium, vitamin D and even agents like zoledronic acid or denosumab)(10-14).
Metastatic. Endocrine therapy is fairly well supported, with tolerable side effects, and should be given in patients with non-visceral or asymptomatic, and with not high-volume visceral tumours, especially in patients with suggestive factors for good response (indolent disease, old age, long disease free interval).
There is also the option of fulvestrant, after progression after antiestrogen therapy. The combination of fulvestrant and anastrozole yelded contradictory results, one study being in favor (S0226), while two studies failed to show benefit (SOFEA and FACT).
Another combination, a steroidal AI (exemestane) and a mTOR (mamalian target for rapamycin) inhibitor (everolimus), showed benefit in the BOLERO-2 study in patients who progressed within 12 months on steroidal AI, or any time on tamoxifen.
There is a benefit to switch non-steroidal AI (like anastrozole) with steroidal AI (like exemestane) after disease progression, if not facing visceral crisis(15).
A promising therapy is available for ER + and HER 2- patients - palbociclib -, a selective cyclin-dependent kinase CDK4 and CDK6 inhibitor. The results of PALOMA-2 trial published in November 2016 showed a significant longer progression-free survival in patients on palociclib in combination with letrozole compared to patients on letrozole alone. However, the addition of palciclib caused higher rates of myelotoxic events in the study (along with fatigue, nausea, mouth sores, hair loss, and diarrhea). For patients who already progressed on an AI, palbociclib can be given along with fulvestrant(16).
As a perspective, MONALLESA-2 trial showed that ribociclib, a second generation CDK 4/6 inhbitor, and even the newer abemaciclib show even more promising results(17).
Resistance to hormonal treatment
Despite good tolerance and response obtained, primary and secondary resistance to hormonal treatment is a concerning reality; phase III studies show that in metastatic breast cancer with positive hormone receptors, only one third of patients have radiological response after IA. And even in the patients who initially respond, at some point they all develop resistance to treatment, progression, and finally death(18,19).
There are several hypotheses for acquired hormonal resistance: altered expression of ER coregulators, downregulation of ER expression, ER mutations and ligand-independent activation of ER - probably, in real life situations experiencing a combination of all above.
It is well known that tumours exhibiting HER2 (human epidermal growth factor receptor 2) are more aggressive and have the worst prognostic. There is evidence suggesting that HER family like HER 1-4, and especially overexpression of HER 2, offers intrinsec resistance to hormonal treatment, thus sustaining the rationale of using also targeted treatment for this case(20-22). Also, there seems to be a place for liquid biopsies in monitoring response to hormonal treatment and prognosis (worse for patients identified with ER mutations by this method)(23). Further studies are needed for identifing and characterizing mechanisms of resistance and methods to overcome them.
In treating breast cancer, every treatment has its use and rationale. It is obvious that a hormonal treatment with low adverse reaction is preferred for most of the patients, even in the presence of visceral metastasis (asymptomatic). Choosing the optimal sequence is still a challenge when talking about benefits/adverse reactions and accessibility to certain drugs. The further development of molecular profiling (some already available in certain areas - MammaPrint, Oncotype Dx), biomarkers and techniques involving circulating tumour cells seem to bring us closer to the ideal of personalized medicine, where patients receive the treatment that yields the best results for them.