First-Line Treatment for Metastatic ER+ HER2- Breast Cancer

First-Line Treatment for Metastatic ER+ HER2- Breast Cancer

Presentation

In 2022, a 58-year-old postmenopausal woman with a personal history of breast cancer presented with sternal pain and cough at her follow-up appointment. She had initially been diagnosed with stage I ER+ HER2- disease (IHC 0) at age 51. Genetic testing revealed that she did not have BRCA1/2 germline mutations. At the time of her initial diagnosis, she underwent a lumpectomy along with radiation and was prescribed 5 years of adjuvant letrozole treatment, which she completed. 

Clinical Workup 

A chest/abdomen/pelvis CT was negative for visceral disease but revealed sclerotic bone lesions. A bone scan showed uptake in the sternum, scapula, lumbar spine, and iliac crest, and an iliac bone biopsy confirmed ER+ HER2- metastatic breast cancer. Next-generation sequencing on the bone biopsy sample was negative for any targetable mutations, such as ESR1 somatic mutations.

Treatment

Currently, the typical front-line systemic therapy for metastatic ER+ HER2- disease is an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) in combination with a CDK4/6 inhibitor.¹ There is not a consensus on the choice of CDK4/6 inhibitors as there were some differences in the study populations in the phase III randomized clinical trials.² In phase III randomized controlled trials, ribociclib and endocrine therapy have shown overall survival (OS) benefit in the first-line setting.^3,4 Additionally, recent results of the phase III MONARCH 3 trial showed a clinically meaningful absolute improvement in median OS when abemaciclib was added to a nonsteroidal aromatase inhibitor in the front line for this disease type.⁵

This patient received letrozole and ribociclib, a CDK4/6 inhibitor, as first-line treatment for her metastatic disease. To treat her bone metastases, the patient was given denosumab 120 mg SQ every 4 weeks. We monitored her calcium levels, and she was given calcium and vitamin D supplementation.

Side-Effect Management: The AP’s Role

It is important for APs to be aware of and to monitor for side effects associated with combination aromatase inhibitor and CDK4/6 treatment. In the phase III randomized, double-blind, placebo-controlled MONALEESA-2 trial, the combination of ribociclib plus letrozole was generally well tolerated. Neutropenia was the most common grade 3 or 4 adverse event, which occurred in 63.8% of patients who received ribociclib vs. 1.2% of patients who received placebo. Hepatobiliary toxic effects occurred in 14.4% of patients who received ribociclib vs. 4.8% of patients who did not, and prolonged QT interval occurred in 4.5% vs. 2.1% of patients, respectively.¹

Because of this risk of prolonged QT interval, we monitored the patient’s electrocardiograms (ECGs) and electrolytes prior to starting therapy and periodically throughout treatment. For ribociclib, the package insert recommends ECGs and electrolytes be measured before treatment. ECGs should be repeated on Day 14 of the first cycle and at the beginning of the second cycle. Additionally, electrolytes should be monitored at the beginning of the first 6 cycles and as clinically indicated.⁶ For this medication, our standard practice is to follow these recommendations.

We also coached the patient on the importance of adherence to oral medications. Inconsistency or poor adherence can reduce the therapeutic benefit of the drug or lead to increased mortality. It can also cause clinicians to incorrectly assume that the drug is not working correctly and unnecessarily change the treatment plan. This can lead to poorer outcomes and be particularly problematic in patients for whom there are limited treatment options.⁷

This patient’s treatment has been generally well tolerated and as of the time of reporting she has not required a dose reduction. After her second week of treatment, she had a low neutropenic fever, but she was able to continue treatment without incident. Since then, her counts have recovered and have been stable. Although the patient has experienced increased fatigue, it does not affect activities of daily living. There are many recommendations that APs can give to patients who are experiencing fatigue. These include practicing good sleep habits, engaging in exercise and physical activity, eating small meals throughout the day, and increasing water intake.⁸ This patient has found that staying active and walking approximately 1.5 to 2 miles a day has helped combat her fatigue. The patient has also experienced hair thinning and arthralgia in her knees from the letrozole. The arthralgia is worse upon awakening but improves with daily movement. She is currently is receiving acupuncture in the clinic once a week and finds this helpful.

References 

1. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386:942-950  
2. National Comprehensive Cancer Network. Invasive Breast Cancer Version 4.2024. Published July 3, 2024. Accessed August 27, 2024 https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 
3. Lu Y, Im S, Colleoni M, et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: A phase III randomized clinical trial. Clin Cancer Res. 2022;28:851-859 
4. Neven P, Fasching PA, Chia S, et al. Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant. Breast Cancer Res. 2023;25:103  
5. U.S. Food and Drug Administration. Kisqali (ribociclib) prescribing information. Published February 2022. Accessed August 27, 2024 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209092s013,209935s021lbl.pdf 
6. Levit LA, Arora S, Kluetz PG, Magnuson A, Rahman A, Harvey RD. Call to action for improving oral anticancer agent adherence. J Clin Oncol. 2022;40:1077-1080. 
7. National Cancer Institute. Fatigue. Accessed August 27, 2024. https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue