EA1242 - A Phase 3 Trial of Rx Therapy Guided by Genomic Risk Assessment For High Anatomic Stage ER+/HER2- Breast Cancer with RS≤25 (RxFINE-Low)

Routine utilization of the Oncotype DX Breast Recurrence Score® test has enabled clinicians to identify patients with newly diagnosed early-stage, estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer who derive little to no benefit from the addition of chemotherapy to endocrine therapy. The landmark TAILORx and RxPONDER trials provided prospective validation that most postmenopausal women with low genomic risk (Recurrence Score 0-25) and node-negative (N0) or limited node-positive (N1) disease do not experience a clinically meaningful reduction in recurrence risk with chemotherapy and may safely forgo this treatment. [1] [2]

However, gene expression assays have not yet been prospectively validated to predict chemotherapy benefit in patients with early ER+/HER2− breast cancer and high anatomic stage disease. Currently, Medicare coverage for the Oncotype assay for patients with ER+/HER2- breast cancer is generally limited to patients with node negativity or limited node-positive disease (1-3 lymph nodes), with variability across payers and regions, and does not typically extend to patients with higher anatomic stage disease.

Most patients with tumors larger than 50 millimeters (T3) or more than 3 positive lymph nodes (N2) were ineligible for TAILORx or RxPONDER, as those studies were designed to evaluate the benefit of chemotherapy in patients with lower anatomic stage disease. As a result, only a small proportion of patients with high anatomic risk can obtain testing.

Patients in this group are routinely prescribed systemic chemotherapy by default based exclusively on anatomic risk. At the same time, advances in endocrine therapy, such as the addition of CDK4/6 inhibitors like ribociclib succinate, have demonstrated improved outcomes, prompting questions about the necessity of chemotherapy when these therapies are used to prevent recurrence. Leading breast cancer researchers note that “questions remain regarding the role of adjuvant chemotherapy in patients who do not meet the current criteria for genomic assay utilization, for example, those with large tumors or N2/3 disease.” [3]

The EA1242/RxFINE-Low trial is designed to address the lack of randomized prospective data regarding the use of the 21-gene recurrence score (RS) in patients who present with high anatomic stage disease. RxFINE-Low is a randomized phase 3 trial enrolling approximately 2,000 postmenopausal women and men with high anatomic stage ER+/HER2− breast cancer and an RS of 0–25 who have completed surgery.

The primary objective of RxFINE-Low is to determine whether patients who receive an aromatase inhibitor plus the CDK4/6 inhibitor ribociclib succinate, without chemotherapy, will have recurrence and survival outcomes that are similar (noninferior) to those who do receive adjuvant chemotherapy followed by the same treatment. The primary endpoint is invasive breast cancer-free survival.

Participants will be randomized 1:1 to receive adjuvant chemotherapy or no chemotherapy. Then, all patients will receive adjuvant endocrine therapy with an aromatase inhibitor (anastrozole, exemestane, or letrozole) in combination with ribociclib. The NATALEE and monarchE trials demonstrated that patients with higher anatomic stage ER+/HER2- breast cancer who received CDK4/6 inhibitors had a lower risk of recurrence.[4] [5] In September 2024, the US Food and Drug Administration (FDA) approved ribociclib in combination with an aromatase inhibitor in the adjuvant setting, based on the NATALEE data.

Secondary objectives include comparing 5-year invasive disease-free survival, distant disease-free survival, overall survival, and breast cancer-specific survival. Short-term and long-term toxicity will be evaluated. Tumor tissue will be banked for future research. Key eligibility criteria include a diagnosis of ER+ (>10% ER expression), HER2- breast cancer without evidence of distant metastases, and RS 0-25. Patients must have completed their primary surgery, and post-operative pathologic staging must show one of the following based on the AJCC Cancer Staging System Manual, Eighth Edition:

• pT0-T3 with 3 positive lymph nodes on the same side of the body (ipsilateral) and no planned axillary (armpit) lymph node dissection
• pT0-T3 with N2 or N3
• pT3 with N0-N3

Regardless of outcome, this study will provide important data to guide treatment decisions for the high anatomic stage, low genomic risk population of patients with early ER+/HER2- breast cancer. If the hypothesis for RxFINE-Low is not confirmed, the study will show that chemotherapy adds clinically meaningful benefit to treatment with optimal endocrine therapy and a CDK4/6 inhibitor. If the study hypothesis is confirmed, treatment guidelines will change and genomic risk assessment to guide therapy for this population will be recommended.

The study chair for this trial is Nancy Chan, MD (New York University/Perlmutter Cancer Center at NYU Langone), and the co-chair is Alexandra Thomas, MD (Duke University Medical Center). The community co-chair is Thomas Saphner, MD (Vince Lombardi Cancer Clinic).

[1] Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. The New England Journal of Medicine. 2018;379(2):111–121. DOI: 10.1056/NEJMoa1804710.

[2] Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. The New England Journal of Medicine. 2021;385:2336–2347. DOI: 10.1056/NEJMoa2108873.

[3] Thomas A, Mayer EL, DeMichele A, et al. Further Optimizing Care of Patients With Operable Hormone Receptor–Sensitive Breast Cancer. Journal of Clinical Oncology. 2025;43(5):487–491. DOI: 10.1200/JCO.24.01080.

[4] Slamon DJ, Fasching PA, Patel R, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. The New England Journal of Medicine. 2024. DOI: 10.1056/NEJMoa2305488.

[5] Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive Early Breast Cancer (monarchE). Journal of Clinical Oncology. 2020;38(34):3987–3998. DOI: 10.1200/JCO.20.02514.