Skipping Hormone Therapy in Low-Risk Early Breast Cancer

No Endocrine Therapy in Small HR⁺/HER2- Low Risk Luminal A Early Breast Cancer, a Single-arm De-escalation Trial

The goal of this clinical trial is to determine whether a selected population of women with early-stage, low-risk breast cancer can avoid hormone therapy without increasing their risk of relapse. It will also evaluate the prognosis of these participants compared to participants who received standard treatment with hormone therapy in another study, estimate the risk of specific recurrence, cardiovascular and bone health, and participants' quality of life.

All participants will have undergone surgery and possibly radiation therapy, but unlike standard care, they will not receive hormone therapy afterward. Participants will be enrolled for two years and followed for up to five years after the last participant is enrolled in the trial to monitor for long-term cancer recurrence.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) tumors represent the predominant subtype and are generally associated with favorable outcomes. Adjuvant endocrine therapy (ET), including tamoxifen and aromatase inhibitors, constitutes a cornerstone of treatment for HR+/HER2- early breast cancer and has demonstrated reductions in recurrence and mortality in large randomized trials and meta-analyses. However, these benefits were mainly established in populations including patients with a broader spectrum of recurrence risk.

The implementation of mammography screening programs has increased the detection of small, early-stage breast cancers, including tumors with excellent prognosis and very low risk of recurrence. In postmenopausal women with small node-negative Luminal A tumors, recurrence rates are particularly low, raising concerns regarding potential overtreatment and the balance between treatment benefit and toxicity.

Although ET is effective, its long-term administration is associated with substantial treatment burden and persistent toxicities, including musculoskeletal symptoms, vasomotor symptoms, fatigue, sexual dysfunction, mood disturbances, and bone loss. These adverse effects may significantly affect quality of life and contribute to treatment discontinuation. Observational data have suggested that ET-related quality-of-life impairment may persist longer than chemotherapy-related effects, particularly in postmenopausal women.

Retrospective studies have suggested that the absolute benefit of ET may be limited in selected patients with very low-risk disease, especially among older women with small, low-grade HR+/HER2- tumors. Furthermore, simulation models estimating individualized treatment benefit indicate that the absolute overall survival gain associated with ET in some low-risk subgroups may be minimal, with high numbers needed to treat.

Advances in biological characterization have enabled identification of Luminal A tumors, characterized by strong hormone receptor expression, low proliferative activity, and favorable prognosis. Combining biological characteristics with clinicopathological features such as age, tumor size, grade, and nodal status allows the identification of a subgroup of postmenopausal patients with exceptionally low risk of relapse.

NoELA was developed to prospectively evaluate a therapeutic de-escalation strategy consisting of omission of adjuvant ET in postmenopausal women presenting with very low-risk HR+/HER2- early breast cancer with Luminal A phenotype. The study focuses on patients expected to derive limited benefit from ET while remaining exposed to its long-term toxicity burden.

The study also aims to generate evidence supporting more individualized treatment strategies and improved shared decision-making by better quantifying the risk-benefit balance of ET omission in this population. In addition, comparison with external real-world data derived from patients treated with standard ET will help contextualize outcomes and improve the external validity of the findings.

Inclusion Criteria:

• Postmenopausal (underwent bilateral oophorectomy or non-chemo induced amenorrhea for 12 or more months) female participant ≥60 years of age.
• New diagnosis of invasive carcinoma of the breast (ductal, tubular or mucinous) with primary tumor ≤1 cm on microscopic exam with no evidence of nodal or distant metastatic disease.
• Contralateral breast described as BI-RADS (Breast Imaging-Reporting And Data System) 1 or 2 in diagnostic imaging.
• Negative axillary node involvement by sentinel node biopsy or axillary node dissection (pN0) or Clinically negative axillary node involvement (cN0) after mandatory ultrasound exploration without surgical exploration of the axilla if Breast Conservative Surgery (BCS) was performed.
• Estrogen Receptor (ER) positive (≥ 50%) and Progesterone Receptor(PR) positive (> 20%), Ki67 low (≤15%) and HER2 negative (IHC or In Situ Hybridization approach) according to ASCO (American Society of Clinical Oncology) criteria.
• Histological grade scored on the invasive component, 1 or 2 if pT1a or grade 1 if pT1b.
• Treated by mastectomy or BCS with microscopically clear resection margins defined as "no-ink on tumor" or ≥1 mm for invasive and non-invasive disease or no residual disease on re-excision.
• If BCS was performed, participants must have received or have scheduled adjuvant local radiotherapy (RT) within 3 months after surgery
• No indication of adjuvant chemotherapy.
• The participant is willing and able to comply with the protocol for the duration of the study, including scheduled visits, treatment strategy, laboratory tests and other study procedures.
• Participants must be affiliated with a Social Security System (or equivalent).
• The participant must have signed a written informed consent form before any trial-specific procedures. When the participant is physically unable to give written consent, an impartial witness of her choice, independent from the investigator or the sponsor, can confirm the participant's consent in writing.

Exclusion Criteria:

• Have received any neo-adjuvant treatment, including hormone therapy and chemotherapy.
• Have received or are eligible for adjuvant chemotherapy.
• Absolute contraindication for RT in case of BCS or patients who were treated with partial breast irradiation.
• Have been treated with mastectomy and with adjuvant radiotherapy received or scheduled.
• Invasive lobular breast cancer.
• Bilateral breast cancer or history of other invasive ipsi- or contralateral breast cancer.
• Multifocal or multicentric disease.
• Disease limited to microinvasion only (< 1 mm).
• Evidence of lymphovascular invasion.
• History of non-breast cancer malignancies if not disease-free for > 5 years and considered low risk of recurrence except for treated carcinoma in situ of the cervix, endometrium or colon, melanoma in situ and basal or squamous cell carcinoma of the skin.
• Non-malignant severe disease associated with a life expectancy < 10 years.
• Women with BRCA1, BRCA2 or other high-risk breast cancer predisposing deleterious germline mutations.
• Enrolled in another therapeutic study within 30 days prior to inclusion.
• Unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
• Persons deprived of their liberty or under protective custody or guardianship.