Managing the Effects of Estrogen Deprivation

Ruta Rao, MD

A growing body of research has demonstrated that 5 to 10 years of adjuvant endocrine therapy (ET) plus ovarian function suppression (OFS) in patients with estrogen receptor (ER)-positive breast cancer reduces disease recurrence and mortality. However, despite this proven benefit, adverse events (AEs) associated with ET plus OFS may have a negative impact on patients’ quality of life. If not managed properly, some AEs may be irreversible and lead to poor survival outcomes.¹ These AEs impact multiple organ systems, complicating care and management strategies.¹

Hot flashes, a vasomotor symptom, affect approximately 80% of patients treated with tamoxifen and 93% of patients receiving OFS therapy. Several strategies can be implemented to manage these symptoms, including behavioral therapy and medications. Selective serotonin reuptake inhibitors (SSRIs), clonidine, gabapentin, oxybutynin, and the selective neurokinin-3 receptor antagonist, fezolinetant, have been investigated for the management of vasomotor symptoms with variable outcomes and AE profiles.^1-3

Arthralgias affect up to 46% of patients receiving aromatase inhibitors (AIs) and can lead to treatment discontinuation in one-third of patients. Treatment options may involve switching to a different AI or utilizing various pharmacologic (duloxetine, vitamin B12, zoledronic acid) and nonpharmacologic (physical activity, acupuncture) approaches.¹

Metabolic disorders are common among patients receiving AIs or tamoxifen include weight gain, diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Lifestyle-based interventions (eg, physical exercise, healthy diet) are effective in managing many of these AEs.¹

The hypoestrogenic state induced by OFS therapy can result in genitourinary syndrome of menopause (GSM), which encompasses symptoms such as vaginal dryness, dyspareunia, and dysuria. Several approaches can be utilized to reduce the impact of these symptoms on quality of life, including elimination of irritants, avoidance of energy-based vaginal treatments, and use of moisturizers and lubricants with sexual activity.³ Vaginal estrogen is considered the most effective treatment for GSM as it promotes Lactobacillus recolonization, increases vaginal blood flow, heightens sexual response, and improves mucosal thickness and elasticity.³

Breast cancer treatments are associated with significant challenges to maintaining patients’ fertility. Approximately 10% of new breast cancer cases are diagnosed in women of reproductive age, many of whom have not yet completed their families. Although current guidelines recommend fertility counseling and family planning referral, overall utilization of these services remains low.³ The POSITIVE trial, which investigated the interruption of ET ± OFS to attempt pregnancy after breast cancer, showed that among select women with ER-positive early breast cancer, temporary interruption of ET ± OFS for purposes of attempting pregnancy did not confer a greater short-term risk of breast cancer events.⁴ However, barriers to fertility preservation around the United States exist. For instance, only 13 states in the United States mandate insurance coverage for family planning.³

Bone health is another major concern to ET ± OFS in breast cancer. Estrogen deprivation due to ET ± OFS in premenopausal and postmenopausal women accelerates bone turnover, leading to decreased bone density and increased risk of fractures—effects that persist even after treatment discontinuation.⁵ Evidence-based use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer is recommended.⁵ Many of these therapies are associated with AEs that require monitoring and mitigation strategies.⁵

Alopecia, fatigue, insomnia, and psychosomatic symptoms such as generalized pain, cognitive dysfunction, and mood disorders are common AEs associated with ET plus OFS that can be managed through pharmacologic and nonpharmacologic approaches.¹ Psychosomatic symptoms are reported by more than one-third of patients on ET for early breast cancer. Depression and anxiety can be controlled by SSRIs.¹ In summary, proactive management of toxicities in ET is important as these toxicities can impact a patient’s physical, psychosocial, and emotional well-being, ultimately affecting adherence to therapy and disease outcomes.

References

1. Cucciniello L, Garufi G, Di Rienzo R, et al. Estrogen deprivation effects of endocrine therapy in breast cancer patients: incidence, management and outcome. Cancer Treat Rev. 2023;120:102624.
2. Ferreira AR, Meglio AD, Pistilli B, et al. Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis. Ann Oncol. 2019;30:1784-1795.
3. Lambertini M, Arecco L, Woodard TL, et al. Advances in the management of menopausal symptoms, fertility preservation, and bone health for women with breast cancer on endocrine therapy. Am Soc Clin Oncol Educ Book. 2023;43:e390442.
4. Partridge AH, Niman SM, Ruggeri M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656.
5. Eisen A, Somerfield MR, Accordino MK, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: ASCO-OH (CCO) Guideline Update. J Clin Oncol. 2022;40:787-800.