Endocrine therapies for breast and prostate cancers

What is endocrine therapy?

Endocrine therapy is used to treat cancers that use hormones or hormone signaling pathways for growth or survival. At the cellular level, endocrine signaling in cancer cells leads to increased cell proliferation, decreased time available for DNA repair, and increased risk of mutation.⁴ Endocrine therapy primarily works by interfering with endocrine signaling, blocking hormone synthesis, or targeting hormone receptors.^5,6 In the adjuvant setting, these therapies can improve overall survival and decrease risk of cancer recurrence, whereas in the metastatic setting, they might reduce symptom burden.^7,8 The type and duration of endocrine therapy is determined by cancer stage at diagnosis, molecular characteristics, prognostic indicators, cancer genomics, endocrine resistance, and tolerance of adverse toxic effects.

Endocrine therapies include corticosteroids, thyroid hormones, somatostatin analogues, and reproductive hormones. Corticosteroids, frequently combined with chemotherapy to increase their effectiveness, are used in the treatment of hematologic cancers (ie, leukemias, lymphomas, and multiple myelomas).⁵ Thyroid hormones (levothyroxine) are used to inhibit thyroid growth following surgery or radiotherapy for thyroid cancers, or as hormonal replacement therapy after thyroid gland resection.⁹ Somatostatin analogues (octreotide) are a cornerstone treatment for neuroendocrine tumours and, in particular, reduce symptom burden associated with carcinoid syndrome.⁸ Finally, and our focus here, reproductive hormones are frequently used to treat cancers requiring male or female hormones to grow, such as breast and prostate cancers.

Endocrine therapy in breast cancer

More than 75% of breast cancers are driven by either estrogen or progesterone.¹⁰ Compared with breast cancers that are not hormone receptor–positive, estrogen receptor–positive or progesterone receptor–positive breast cancers are usually associated with improved survival.¹¹ Endocrine therapy is a cornerstone treatment in both adjuvant and metastatic settings of hormone receptor–positive breast cancers; it is also sometimes used as a neoadjuvant therapy. Choice of endocrine regimen is typically determined by clinical, pathologic, and genetic factors, including menopausal status. The main breast cancer endocrine therapies are selective estrogen receptor modulators (eg, tamoxifen), aromatase inhibitors (eg, letrozole, anastrozole, exemestane), and ovarian suppression (ie, via gonadotropin-releasing hormone agonists or surgery). In the adjuvant setting, the choice of endocrine therapy is further determined by low-risk versus high-risk categories, with patients younger than 35 years at diagnosis or needing adjuvant chemotherapy following surgery categorized as high risk (Figure 1).¹¹ Other newer therapies, most used in the metastatic setting, include cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitors (eg, ribociclib, palbociclib), selective estrogen receptor degraders (eg, fulvestrant), and mTOR (mammalian target of rapamycin) inhibitors (eg, everolimus).

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Figure 1.

Algorithm for choice of endocrine therapy for breast cancer in the adjuvant setting

Premenopausal patients. In the adjuvant setting, for premenopausal patients at standard risk, tamoxifen is the first-line recommended agent at an oral dose of 20 mg daily for a minimum of 5 years.¹¹ Adjuvant tamoxifen therapy for 5 to 10 years is associated with a statistically significant absolute breast cancer mortality reduction at 15 years (mean [SD] 9.2% [1%]).^12,13 For premenopausal patients at high risk of recurrence, tamoxifen or an aromatase inhibitor is recommended in addition to ovarian suppression based on a discussion of risks and benefits with the patient.¹¹

Clinical pearl: Given the risk of inducing estrogen production due to ovarian stimulation, aromatase inhibitors should not be used as a single agent in premenopausal patients. In high-risk patients, aromatase inhibitors coupled with ovarian suppression might be used. Recurrence of menstrual periods during aromatase inhibitor therapy warrants measurement of serum estradiol levels and urgent referral back to an oncology specialist.

Postmenopausal patients. In the adjuvant setting, aromatase inhibitors are the endocrine therapy of choice in postmenopausal patients, for a minimum duration of 5 years. A daily oral dose of letrozole at 2.5 mg, anastrozole at 1 mg, or exemestane at 25 mg can be used. In comparison with tamoxifen, aromatase inhibitors are associated with a statistically significant absolute risk reduction of recurrence at 10 years (3.6%) and an increase in overall survival (2.1%).¹⁴

Clinical pearl: Breast cancer recurrence reduction has been demonstrated in patients who switch from tamoxifen to an aromatase inhibitor within the first couple of years of endocrine therapy (2.0%).¹⁴ Therefore, patients who reach menopause after 2 to 3 years of taking tamoxifen should be considered for a substitution in their endocrine regimen to aromatase inhibitors.

Endocrine therapy duration. The duration of adjuvant endocrine therapy is typically 5 years.¹⁴ Endocrine therapy extension for up to 10 years with either tamoxifen or an aromatase inhibitor might further reduce the risk of breast cancer recurrence in high-risk patients.¹⁴ Potential benefits versus potential adverse effects of extended therapy should be carefully assessed by an oncology specialist.¹¹

Side effects and management. An overwhelming majority of patients experience burdensome side effects, causing suboptimal adherence or therapy discontinuation in approximately 30% of patients.³ Primary care providers’ role in active screening and management of these side effects is imperative to alleviate symptom burden, optimize adherence, and prevent rare but potentially serious complications.¹¹ Hot flashes are one of the most frequently reported side effects of tamoxifen, occurring in nearly 80% of patients.¹⁵ The mainstay of management includes promotion of lifestyle changes (diet, dressing, bedding) and use of a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.¹¹ Half of patients experience bothersome arthralgias caused by aromatase inhibitors.¹¹ Regular physical exercise, massage therapy, and acupuncture can help alleviate these side effects; the substitution of another aromatase inhibitor might also be helpful.¹¹ Osteoporosis can also result from aromatase inhibitor therapy; supplemental calcium and vitamin D, as well as routine bone mineral density tests, are the mainstay of management.¹¹ Table 1 provides a summary of common side effects of breast cancer endocrine therapies and their respective management.¹¹

Endocrine therapy in prostate cancer

Approximately 75% of prostate cancer cases are diagnosed at an early stage; the remainder present either with regional nodal disease or as metastatic upon diagnosis.¹ Androgen deprivation therapy is a mainstay treatment of prostate cancer and has resulted in a considerable decline in associated mortality rates since 1994.¹ More specifically, androgen deprivation therapy is used as the primary systemic therapy for regional or advanced disease and is combined with radiotherapy as neoadjuvant, concurrent, or adjuvant therapy in localized or locally advanced prostate cancers.¹⁶ Treatment agents can block the action or the production of androgen throughout the body, or reduce its production from the testicles, thereby reducing cancer cell growth.¹⁷ Androgen deprivation can be achieved either surgically (orchiectomy) or medically. Medical therapies include gonadal androgen ablation through luteinizing hormone–releasing hormone agonists (eg, leuprolide, triptorelin, goserelin) or luteinizing hormone– releasing hormone antagonists (eg, degarelix, relugolix); androgen receptor antagonists (eg, bicalutamide, enzalutamide, apalutamide, darolutamide); and adrenal androgen synthesis inhibitors (abiraterone acetate, ketoconazole).¹⁸ Medical castration is monitored by assessing circulating testosterone levels. Choice of prostate cancer treatments is determined by a multitude of factors, including stage and grade of cancer at diagnosis, risk of disease progression, expected survival, comorbidities, and family history, as well as patient preference and the side effect profiles of proposed treatments.^16,17 Moreover, as initiation of luteinizing hormone–releasing hormone agonists is associated with a testosterone flare, the use of an androgen receptor antagonist is recommended in the first 2 to 4 weeks of therapy.^16,18

In patients with intermediate- to high-risk disease, androgen deprivation therapy combined with radiotherapy has been shown to improve survival. Duration of therapy is typically 4 to 6 months for those with intermediate risk, whereas those at higher risk receive continuous androgen deprivation therapy to treat occult systemic disease and reduce the risk of recurrence.^16,19 However, androgen deprivation therapy is most often used in the metastatic prostate cancer setting in an intermittent or continuous fashion.¹⁹ Worthy of mention, abiraterone has been shown to increase the level of adrenocorticotropic hormone owing to decreased production of cortisol, leading to substantial adverse effects from mineralocorticoid excess (eg, hypertension, fluid retention, hypokalemia).²⁰ To mitigate these adverse effects, glucocorticoids are administered in combination with abiraterone: 5 mg of oral prednisone twice daily is the standard formulation.^16,20 Table 2 provides a summary of prostate cancer agents, including their mechanism of action and indications.²⁰

Clinical pearl: Androgen deprivation therapy is not recommended as monotherapy in localized prostate cancer, except in the presence of a contraindication to curative local therapy, such as comorbidities or a prognosis of less than 5 years.¹⁶

Side effects and management. Although androgen deprivation therapies have improved oncological outcomes, they are nonetheless associated with several frequently debilitating side effects that adversely affect quality of life.^17–19 In turn, care of patients on androgen deprivation therapy is best provided by a multidisciplinary approach that includes active collaboration between the treating specialists and primary care providers.^18,19 Androgen deprivation therapy can adversely impact various organ systems and affect bone health, sexual function, and mental health, and lead to cardiovascular disease and metabolic consequences.^18,19 Routine screening and prompt management of these potential side effects are of primary importance.¹⁸ Table 3 outlines common adverse effects of prostate cancer endocrine therapies and the management of each.¹⁸