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Ongoing Care of a Woman with Breast Cancer on an Aromatase Inhibitor

Author: Stephanie V. Blank, MD

Editor: Julie A. Zemaitis DeCesare, MD

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Breast cancer is the second leading cause of cancer death among women in the United States. Seventy five percent of breast cancers are estrogen receptor (ER) or progesterone receptor (PR) positive, and the majority of these are treated with adjuvant hormonal therapy. Aromatase inhibitors (AIs) are used to treat hormone receptor positive breast cancers in postmenopausal women. In randomized controlled trials and meta-analyses, AIs have been found to be more effective in preventing breast cancer recurrence than tamoxifen. Letrozole is a reversible blocker of aromatase that competes with androgens for aromatase, an enzyme present in adipose tissue which converts androstenedione to estrone. Through this pathway, postmenopausal women produce 100mcg of estrone daily, and more if they are obese.

Most women on letrozole experience controllable side effects. However, in 10-20% of cases side effects necessitate discontinuation. Management of the woman with breast cancer on letrozole should include the control of AI-related symptoms sufficient to allow ongoing treatment as well as quality of life.

There are a number of side effects related to lack of estrogen at aromatase-targeted tissue:

Gynecologic:  Aromatase inhibitors can exacerbate menopausal symptoms. AIs do not increase the risk of endometrial neoplasia, and no specific monitoring is necessary. Women on AIs are more likely to experience vaginal dryness, dyspareunia, and decreased libido. Vaginal or vulvar symptoms can be treated locally with moisturizers. The use of vaginal estrogen may be considered in select symptomatic women who fail non-hormonal treatment after review of risks and benefits. Vasomotor symptoms may be treated with behavioral therapy or non-hormonal pharmacologic therapy, such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antiepileptics.

Musculoskeletal:  Bone and joint issues include decreased bone mineral density, increased fracture risk, and musculoskeletal pain. Women on AIs should have pretreatment evaluation of fracture risk including bone mineral density (BMD) measurement. Modifiable risk factors such as smoking, excess alcohol, chronic steroid use, and inactivity should be corrected when possible. Patients should be encouraged to have appropriate calcium intake, diet, and weight bearing exercise to encourage bone health. Vitamin D deficiency should be monitored using 25-hydroxyvitamin D levels. If BMD reveals bone loss, bisphosphonates or other appropriate therapy should be started. Vitamin D deficiency should be corrected prior to the initiation of bisphosphonates. Bone mineral density should be followed yearly in patients on AIs.

Denosumab is an alternative treatment for bone loss for patients who do not tolerate or respond to bisphosphonates. Denosumab is a humanized monoclonal antibody to RANKL, a tumor necrosis factor ligand essential for osteoclast function.

Musculoskeletal symptoms including arthralgias and joint stiffness are a common reason for discontinuing AI therapy. Risk factors include obesity, prior chemotherapy, and pre-existing musculoskeletal conditions. Knees, hands, wrists, and shoulders are common sites of pain. Symptoms may be improved by exercise and the use of nonsteroidal anti-inflammatory drugs.

Hematologic and cardiac:  Aromatase inhibitors do not increase the risk of thrombosis, and a history of VTE is not a contraindication to AI use. Some studies suggest AIs, letrozole, in particular, have a negative impact on cardiovascular health and lipid profiles. This association has not been consistent and may be related to a reduced risk in patients treated with tamoxifen compared to patients using AIs.  No additional monitoring is necessary.

Further Reading:

Initial Approval:  June 2013; Reaffirmed 2014, September 2015, Revised March 2017, November 2018; Revised July 2020; Reaffirmed January 2022. Reaffirmed November 2023

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This document is designed to aid practitioners in providing appropriate obstetric and gynecologic care. Recommendations are derived from major society guidelines and high-quality evidence when available, supplemented by the opinion of the author and editorial board when necessary. It should not be construed as dictating an exclusive course of treatment or procedure to be followed.

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