Presenter: Prof. Michael Untch, Head of the Interdisciplinary Breast Cancer Center at Helios Clinic Berlin-Buch, Germany and Prof. Frédérique Penault-Llorca, Centre Jean Perrin, Clermont Ferrand, France.

The introduction of adjuvant CDK4/6 inhibition represents a major advance in the treatment of patients with ER-positive, HER2-negative early breast cancer (eBC), enabling therapy intensification without mandatory chemotherapy.

At the recent webinar, Professor Michael Untch presented 4-year outcome data from the phase III NATALEE trial, demonstrating a significant invasive disease-free survival (iDFS) benefit with Ribociclib in combination with endocrine therapy. Additionally, Professor Frédérique Penault-Llorca reported results from the UNIRAD trial, underscoring the strong prognostic value of EndoPredict in clinically high-risk pre- and postmenopausal patients by identifying a genomic low-risk subgroup with excellent outcomes.

Together, these findings highlight the crucial role of precise risk stratification in optimizing adjuvant treatment strategies for early breast cancer. The approval of the CDK4/6 inhibitor Ribociclib enables physicians to intensify adjuvant treatment for ER+ HER2- early breast cancer patients without necessarily treating them with chemotherapy. In contrast to Abemaciclib, which is indicated in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence, Ribociclib is also indicated for a subset of nodal-negative patients.

Professor Michael Untch, Chief Physician gynecology and obstetrics and Head of the Interdisciplinary Breast Cancer Center at Helios Clinic Berlin-Buch, Germany since 2006, and steering committee member of the phase III NATALEE trial, presented the 4-year outcome data of Ribociclib in this setting.

In NATALEE. adult patients with anatomical stage III, stage IIB, and selected patients with stage IIA ER+/HER2- eBC were included. Patients with stage IIA tumors needed to fulfill the following high-risk criteria1:

In total 5101 patients were randomized 1:1 to receive RIB (400mg/day, 3 weeks on/1 week off for 3 years) plus NSAI (Letrozole or Anastrozole for ≥ 5 years + goserelin in men and premenopausal women) vs. NSAI (Letrozole or Anastrozole for ≥ 5 years + goserelin in men and premenopausal women) alone. Approximately 88% of patients included in NATALEE  received either neoadjuvant or adjuvant chemotherapy.^1,2,3

After 4 years of follow-up a significant iDFS (invasive disease free survival) benefit of 4.9% was observed for the ITT (intended to treat) population with RIB+NSAI (iDFS RIB+ NSAI= 88.5% vs. NSAI= 83.6%; HR= 0.715; p< 0.0001). ²

Although the iDFS benefit was favorable across all key prespecified subgroups such as nodal status or prior chemotherapy, the benefit for patients without prior chemotherapy appeared to be less significant (HR= 0.827).2 When comparing iDFS by nodal status alone, RIB + NSAI showed an increasing magnitude of iDFS benefit over time for N0 as well as for N1-3 patients with a delta of 5.1% and 5% after 4-years of follow-up, respectively. Especially premenopausal patients under the age of 40 y seemed to show a distinct advantage of RIB +NSAI including goserelin.²

100% of the patients screened for UNIRAD fulfilled the criteria of the NATALEE trial design as well, and 40% fulfilled those of MonarchE as illustrated in Table 1.¹

Table 1 : Adapted from Slamon DJ et al Ther Adv Med Oncol 2023, Vol. 15: 1–16

 

Looking into the clinical features of EPclin low-risk patients screened for UNIRAD: 97.1% had pN1 tumors, 2.2% had pN2 tumors, with 66.7% pT1 and 31.4% pT2 tumors. Since these patients had an excellent outcome with chemotherapy and 5-years of NSAI alone, the EPclin low-risk group may not benefit from the addition of CDK4/6i therapy to standard endocrine therapy, although they fulfill the indication criteria of positive lymph node involvement.⁴

The open question remains if some clinically high-risk patients eligible for CDK4/6i treatment may omit previous chemotherapy. This question needs to be addressed by future clinical trials in combination with accurate and reliable risk assessment tools.

To get even more information on this topic from the exciting discussion of our experts, please watch the recording of the webinar.

What`s new for high-risk early Breast Cancer Patients in 2024? – WebinarGeek

Intended use EndoPrecict⁵

The EndoPredict® QS Kit is an in vitro diagnostic product for patients with estrogen-receptor-positive, HER2-negative primary breast cancer to determine the risk of distant recurrence and to estimate the adjuvant chemotherapy benefit. For the intended purpose, the EndoPredict® QS kit may only be applied to RNA samples extracted from formalin-fixed, paraffin-embedded breast cancer tissue.

The EndoPredict® QS Kit is designed for use by experts trained in the assay techniques required for performance of the test and in the application of the system. The results of the EndoPredict® test may be used only in the proper context, together with other established methods and clinical/pathological factors for the prognosis and stratification of patients with breast cancer.
References:

https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf

https://uspl.lilly.com/verzenio/verzenio.html#pi

1. Slamon DJ et al.: Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol 2023
2. Fasching et al.: Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial. JAMA Oncol. 2025
3. Hortobagyi G.N. et al.: A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. ESMO Ann Oncol 2024
4. Penault-Llorca F. et al.: Prognostic value of EndoPredict test in patients with hormone receptor positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial. ESMO Open 2024
5. EndoPredict® QS for QuantStudio™ 5 Dx Instruction Manual Version EN/03 2025