Endocrine therapy drugs or hormonal therapies form an important part of the treatment options for hormone-receptor positive breast cancers. These cancers depend on estrogen and/or progesterone to grow. Endocrine therapy drugs work by blocking the effects of estrogen and progesterone on cancer cells or by lowering hormone levels in the body. Let us explore different types of endocrine therapy drugs and how they work in the treatment of breast cancer.
Types of Endocrine Therapy Drugs
Endocrine Therapy Drugs for breast cancer mainly fall under the following categories:
Aromatase Inhibitors
Aromatase inhibitors are the most commonly used hormonal therapies prescribed after menopause. They work by preventing the conversion of androgens to estrogens in peripheral tissues like fat. This brings down estrogen levels in postmenopausal women. The three main aromatase inhibitors used are:
Anastrozole (Arimidex): It has been shown to be as effective as tamoxifen with fewer side effects. Common side effects include joint pain, fatigue and hot flashes.
Letrozole (Femara): Letrozole is another aromatase inhibitor used as initial treatment or after tamoxifen therapy. It has comparable side effect profile to anastrozole.
Exemestane (Aromasin): Exemestane is given after initial treatment with tamoxifen to further reduce the risk of breast cancer recurrence. Common side effects include joint pain, fatigue and hot flashes.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) work by blocking the effects of estrogen on cancer cells while having estrogen-like effects on other tissues like bone. The main SERM used is:
Tamoxifen (Nolvadex): It remains a mainstay of endocrine therapy for premenopausal and postmenopausal breast cancer patients. It halves the chances of recurrence in estrogen receptor-positive cancers. However, its side effects include hot flashes, vaginal discharge or bleeding, leg cramps and rare chances of uterine cancer, blood clots or stroke.
Estrogen Lowering Drugs
These drugs lower estrogen levels in premenopausal women whose ovaries continue to produce estrogen. They include:
GnRH Analogues: They work by downregulating the action of gonadotropin-releasing hormone from the hypothalamus and reducing ovarian estrogen production. Commonly used drugs are goserelin and leuprorelin injections. Side effects include menopausal symptoms.
Aromatase Inhibitors: Used along with ovarian suppression, they inhibit peripheral conversion. Side effects are similar to those used after menopause.
Tamoxifen: Remains an option for premenopausal women and carries similar side effect profile as in postmenopausal women.
Mechanism of Action
Different endocrine therapy drugs work through distinct mechanisms:
Aromatase inhibitors lower estrogen levels by inhibiting the aromatase enzyme complex which catalyzes the conversion of androgens to estrogens. They find widespread use after menopause when ovaries cease functioning.
Selective estrogen receptor modulators act as agonists on some tissues like bone but antagonists on breast tissue by blocking the binding of estrogens to their receptors.
GnRH analogues act on the hypothalamus-pituitary-ovarian axis and downregulate ovarian estrogen production in premenopausal women.
These mechanisms effectively lower or block the growth stimulus provided by estrogens and progesterone to hormone receptor positive cancers.
Monitoring and Management
Patients on endocrine therapy require monitoring of treatment response and side effects:
– Clinical exam and imaging are carried out periodically to monitor tumor response.
– Bone mineral density scans determine risk of osteoporosis from long term estrogen lowering.
– Lipid profiling and lifestyle advice manage increased cardiovascular risk.
– Menopausal symptoms are managed with lifestyle changes, exercise, vaginal lubricants or local estrogen.
– Medications are used judiciously weighing risks and benefits, optimizing duration, and switching sequential therapies.
Endocrine therapies form a mainstay of treatment for hormone receptor positive breast cancers. Understanding different classes of drugs, their mechanisms and management helps healthcare providers optimize benefits while minimizing toxicity. Research into newer agents and combinations also holds promise to improve outcomes in hormonally-driven breast cancers.
ER Positive Breast Cancer Recurrence with Endocrine Therapy
Despite initial responses seen with endocrine therapies, a significant number of patients eventually experience recurrence of their cancer as it develops resistance to hormonal treatments over time. Let us look at some key factors associated with recurrence in ER positive breast cancer patients on long term endocrine therapy.
Tumor Biology and Phenotype
The inherent biology and phenotype of the tumor determines its behavior to a large extent. Cancers with high levels of ER, PR expression and luminal A molecular subtype tend to respond better to hormonal therapies. PIK3CA gene mutations, high Ki67 levels point towards an increased risk of recurrence.
Treatment and Duration Factors
Switching from tamoxifen to an aromatase inhibitor reduces recurrence compared to tamoxifen alone in postmenopausal patients. However, extending aromatase inhibitor therapy beyond 5 years does not seem to provide substantial additional benefit in terms of recurrence free survival as per recent trials.
Premenopausal patients have higher recurrence rates due to continued ovarian estrogen production even with ovarian suppression. Adjuvant chemotherapy alongside endocrine therapy improves outcomes in high risk premenopausal patients.
Patient Related Factors
Obesity has been linked to higher recurrence risk possibly due to increased aromatase enzyme levels in fat tissue. Lifestyle changes aimed at weight control may help countering this association.
Treatment non-adherence over long follow up periods also adversely impacts outcomes. Risk reduction counselling and regular follow up addresses this important compliance aspect.
Managing Recurrence
For those experiencing recurrence of disease on endocrine therapy, further treatment strategies are guided by tumor characteristics on recurrence biopsy specimen. These may include switching to another hormonal agent, addition of targeted therapies like CDK 4/6 inhibitors or chemotherapy depending on clinical-pathological factors of recurrent disease. Close monitoring for recurrence of ER positive disease continues indefinitely with long term endocrine treatment.
In conclusion, optimizing endocrine therapies at each step right from adjuvant to metastatic settings along with control of modifiable risk factors provides the best chance at preventing or delaying recurrence in ER positive breast cancers. Further research also focuses on developing biomarkers.