patient care perspectives

First-line Therapy for Advanced HR+ HER2- Breast Cancer

by Joseph A. Sparano, MD, FACP


Endocrine therapy remains the foundational treatment for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer. The addition of CDK4/6 inhibitor therapy has also become standard in the treatment of advanced or metastatic breast cancer.

Expert Commentary

Joseph A. Sparano, MD, FACP

Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics
Chief, Division of Hematology and Medical Oncology
Deputy Director
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, NY

“Since estrogen stimulates the growth of estrogen-dependent breast cancer, antiestrogen therapy is the bedrock of the first-line treatment of advanced HR+/HER2- breast cancer.”

Joseph A. Sparano, MD, FACP

HR+/HER2- breast cancer accounts for approximately two-thirds of all breast cancers in the United States. Since estrogen stimulates the growth of estrogen-dependent breast cancer, antiestrogen therapy is the bedrock of the first-line treatment of advanced HR+/HER2- breast cancer. For postmenopausal women, this would generally include either the nonsteroidal aromatase inhibitors anastrozole or letrozole or the steroidal aromatase inhibitor exemestane. For premenopausal women, ovarian function suppression is combined with the aromatase inhibitor. 

Over the last 5 to 7 years, CDK4/6 inhibitors have also become a component of standard therapy for these patients. Initial studies showed that all 3 of the available CDK4/6 inhibitors (ie, palbociclib, ribociclib, and abemaciclib) improve progression-free survival and objective response when added to first-line endocrine therapy. In addition, within the last year or so, several studies have demonstrated that these agents improve overall survival, although this has mainly been observed with ribociclib and abemaciclib, and not consistently with palbociclib. 

Aromatase inhibitor–plus–CDK4/6 inhibitor therapy would generally be the paradigm for patients who present with metastatic breast cancer at their initial diagnosis or for patients who previously had localized disease and experienced relapse while not receiving adjuvant endocrine therapy, which could happen because they had either completed at least a 5-year course of adjuvant endocrine therapy or discontinued adjuvant endocrine therapy because of side effects. For patients who relapsed on an aromatase inhibitor or tamoxifen, they would generally receive fulvestrant plus a CDK4/6 inhibitor. 

Regarding side effects, neutropenia is a main side effect of palbociclib, which became commercially available back in 2015, and ribociclib, which became available a couple of years thereafter; both of these are given on a 3 weeks on, 1 week off schedule that minimizes the neutropenia. In addition, there is the issue of QT interval prolongation with ribociclib, and precautions include cardiac monitoring and electrolyte monitoring as described in the prescribing information. Abemaciclib, the third CDK4/6 inhibitor that is US Food and Drug Administration approved, causes less neutropenia than the other approved CDK4/6 inhibitors and is generally given on a continuous basis, twice daily as opposed to once daily for palbociclib and ribociclib. The most common adverse event that is associated with abemaciclib is diarrhea, which can be severe but is usually mild to moderate and tends to improve with time. All 3 CDK4/6 inhibitors are metabolized primarily by CYP3A and SULT2A1 enzymes and are time-dependent inhibitors of CYP3A. 

Overall, approximately 10% to 20% of patients in the pivotal trials discontinued CDK4/6 inhibitors due to adverse events, and approximately one-third to one-half of patients require dose interruptions or dose reductions with these agents. Fortunately, these dose interruptions and reductions do not seem to adversely affect efficacy.


Elfgen C, Bjelic-Radisic V. Targeted therapy in HR+ HER2− metastatic breast cancer: current clinical trials and their implications for CDK4/6 inhibitor therapy and beyond treatment options. Cancers (Basel). 2021;13(23):5994. doi:10.3390/cancers13235994

Hortobagyi GN, Stemmer SM, Burris HA, et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. doi:10.1016/j.annonc.2021.08.2090

Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663

Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer [published correction appears in JAMA Netw Open. 2020;3(11):e2030492]. JAMA Netw Open. 2020;3(10):e2020312. doi:10.1001/jamanetworkopen.2020.20312

Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—the Penelope-B trial. J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639

McAndrew NP, Finn RS. Clinical review on the management of hormone receptor-positive metastatic breast cancer. JCO Oncol Pract. 2021;18(5):319-327. doi:10.1200/OP.21.00384

Miglietta F, Bottosso M, Griguolo G, Dieci MV, Guarneri V. Major advancements in metastatic breast cancer treatment: when expanding options means prolonging survival [published correction appears in ESMO Open. 2022;7(3):100472]. ESMO Open. 2022;7(2):100409. doi:10.1016/j.esmoop.2022.100409

Munzone E, Pagan E, Bagnardi V, et al. Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials. ESMO Open. 2021;6(6):100332. doi:10.1016/j.esmoop.2021.100332

Rugo HS, Huober J, García-Sáenz JA, et al. Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3 [published correction appears in Oncologist. 2021;26(3):e522]. Oncologist. 2021;26(1):e53-e65. doi:10.1002/onco.13531

Santoni M, Occhipinti G, Romagnoli E, et al. Different cardiotoxicity of palbociclib and ribociclib in breast cancer: gene expression and pharmacological data analyses, biological basis, and therapeutic implications. BioDrugs. 2019;33(6):613-620. doi:10.1007/s40259-019-00382-1

Surveillance, Epidemiology, and End Results Program. National Cancer Institute. Cancer stat facts: female breast cancer subtypes. Accessed April 26, 2023.

Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer [published correction appears in Ther Adv Med Oncol. 2018;10:1758835918810116]. Ther Adv Med Oncol. 2018;10:1758835918793326. doi:10.1177/1758835918793326

More in HR-Positive HER2-Negative Breast Cancer


HR-Positive HER2-Negative Breast Cancer

Expert Perspectives in HR+ HER2- Breast Cancer to Cover Key Topics in HR+ HER2- Breast Cancer Treatment

Expert Perspectives by Tom Iarocci, MD

Expert Perspectives delivers health care providers with insights from key thought leaders on the latest advancements and current practices in medic...READ MORE


HR-Positive HER2-Negative Breast Cancer

Biomarkers of Response in HR+ HER2- Breast Cancer

Clinical Topic Updates by Matthew P. Goetz, MD

Estrogen receptor (ER) expression remains the most important predictive biomarker of response to endocrine therapy in hormone receptor–positive (HR...READ MORE


HR-Positive HER2-Negative Breast Cancer

The Role of Gene Expression Profiling in Breast Cancer Treatment Selection

Clinical Topic Updates by Matthew P. Goetz, MD

Gene expression profiling is an emerging tool to help guide treatment decisions in patients with breast cancer. In particular, it has been used to ...READ MORE

More In Oncology

HER2-Positive Breast Cancer

Recent Developments in HER2-Targeted Therapy

Clinical Topic Updates by Ian Krop, MD, PhD


Prophylactic Strategies in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Expert Roundtables by Sergio A. Giralt, MD; John Koreth, MBBS, DPhil; and Robert S. Negrin, MD