Pragmatic Study to Optimize Neoadjuvant Treatment and Surgical De-escalation in HR+/HER2- Early Breast Cancer Using Oncotype DX and Abemaciclib (VIOLET)

The VIOLET Trial: A Pragmatic Phase II Study to Optimize Neoadjuvant Treatment and Surgical De-escalation in HR+/HER2- Early Breast Cancer Using Oncotype DX and Abemaciclib

This is a pragmatic phase 2 study to determine the proportion of patients with ER+ (≥10%)/HER2- EBC in whom neoadjuvant chemotherapy can be replaced by NET plus abemaciclib based on the results of the ODX RS obtained in the initial diagnostic biopsy and according to the MDT decision and to evaluate the proportion of patients undergoing breast conservative surgery and/or sentinel node biopsy

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Neoadjuvant Therapy; HR Positive; HER2 + Breast Cancer
• Intervention / Treatment: Drug: Abemaciclib

Detailed Description

Women aged 18 years or older with histologically confirmed operable or inoperable ER-positive (>10%)/HER2-negative invasive breast carcinoma (stage II-IIIB), candidate to receive neoadjuvant chemotherapy according to the shared decision of a multidisciplinary tumor board, and who are not eligible to receive upfront breast conservative surgery AND/OR are candidate to lymph node. All eligible patients will undergo ODX RS tumor assessment in the baseline biopsy. They will receive NET plus abemaciclib or NCT for 6 months as per MDT decision, according to tumor stage, tumor histology, patient menopausal status and ODX RS results. At the end of the neoadjuvant treatment, all patients will be discussed again in a multidisciplinary tumor board and a new surgical indication will be given according to the post-treatment clinical and radiological assessment.After surgery, patients who received NET+abemaciclib may receive adjuvant chemotherapy according to the multidisciplinary tumor board indication.dissection.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • MI
    • Milan, MI, Italy, 20156
      • Istituto di Ricerche Farmacologiche Mario Negri IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• female aged 18 years or older
• primary, histologically confirmed diagnosis of invasive breast carcinoma,
• estrogen receptor (ER)-positive tumor, defined as ≥10% by immunohistochemistry and measured as per ASCO/CAP guidelines (Allison et al.2020). Any progesterone receptor expression is acceptable (as per local assessment)
• documented human epidermal growth factor receptor-2 (HER2)-negative tumor as per ASCO/CAP guidelines, assessed locally,
• stage II-IIIB as per AJCC TNM classification (8th edition). Absence of distant metastases (with the exception of tumor detected in internal mammary chain nodes by sentinel node procedure),
• candidate to receive neoadjuvant chemotherapy according to the indication of a multidisciplinary tumor board,
• not eligible to receive upfront breast conservative surgery (but considered potentially eligible to receive a BCS in case of tumor downstaging) AND/OR not candidate to sentinel lymph node dissection because of clinical node positive disease
• Eastern Cooperative Oncology Group Performance Status 0-1,
• The patient is able to swallow oral medications

• normal hematologic parameters:

  a.) absolute neutrophil count ≥ ≥1500/mm3 (1.5 × 10 9/L), b) platelets ≥ 100 × 10 9/L, c)hemoglobin ≥ 8 g/dL (≥ 80 g/L)). Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion

• normal renal function: serum creatinine concentration ≤1.5 ULN or calculated clearance ≥50 mL/min according to the Cockcroft-Gault formula,

• normal liver function:

  a.)serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted., b)AST and ALT ≤ 3 × ULN, c)alkaline phosphatase ≤ 2.5 × ULN,

• women of child bearing potential must have documented negative pregnancy test within 2 weeks (preferably 7 days) prior to study entry and must agree to effective non-hormonal contraception (barrier method - condoms, diaphragm -also in conjunction with spermicidal jelly, or total abstinence) after the pregnancy test and up to surgery. Oral, injectable, or implant hormonal contraceptives or medicated IUD are not allowed during the trial,
• willingness to undergo breast surgery after optimal neoadjuvant treatment, and to provide blood and tumor samples for the study purposes, including the submission for central assessment of Oncotype Dx test.

Exclusion Criteria:

• presence of distant metastases (stage IV) or stage IIIC disease,
• inflammatory or locally-advanced, inoperable breast cancer
• previous invasive ipsilateral breast cancer at any time,

• previous or concomitant invasive malignancy. The exceptions are patients with the following (and only the following) malignancies (previous or concomitant), if adequately treated:

  1. basal or squamous cell carcinoma of the skin,
  2. melanoma in situ,
  3. in situ non-breast carcinoma without invasion,
  4. contra- or ipsilateral in situ breast carcinoma,
  5. non-breast invasive malignancy diagnosed at least 5 years ago and without recurrence,
  6. stage I papillary thyroid cancer,
  7. stage Ia carcinoma of the cervix,
  8. stage Ia or b endometrioid endometrial cancer,
  9. borderline or stage I ovarian cancer
• known history of uncontrolled or symptomatic angina, uncontrolled hypertension (≥ 180/110 mmHg), uncontrolled diabetes mellitus, dyspnea at rest, chronic therapy with oxygen, a New York Heart Association (NYHA) class III or IV congestive heart failure, syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
• females who are pregnant or lactating (lactation has to stop before study entry)
• the patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea),
• The patient has had major surgery within 14 days prior to study entry.
• The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to study entry, or is currently enrolled in any other type of medical research (for example: medical device) judged by the sponsor not to be scientifically or medically compatible with this study.
• The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive])
• contraindications or known hypersensitivity to the trial medication or excipients,
• use of any anti-cancer investigational agents within 30 days prior to expected start of trial treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: chemotherapy (NCT); Neoadjuvant chemotherapy (NCT), including sequential standard regimens with sequential anthracyclines and taxanes,
Experimental: NET plus abemaciclib; neoadjuvant endocrine therapy (NET) plus abemaciclib.	Drug: Abemaciclib; neoadjuvant endocrine therapy (NET) plus abemaciclib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
determine the proportion of patients with ER+ (≥10%)/HER2- EBC in whom neoadjuvant chemotherapy can be replaced by NET plus abemaciclib based on the results of the ODX RS obtained in the initial diagnostic biopsy and according to the MDT decision	the proportion of patients with ER+/HER2- EBC who avoid (neo)adjuvant chemotherapy according to the MDT decision based on the ODX RS assessment in the tumor biopsy specimen and the availability of abemaciclib/ET option for the lower RS group	From the date of the enrollment up to 24 months
evaluate the proportion of patients undergoing breast conservative surgery and/or sentinel node biopsy	the proportion of patients who de-escalate surgery after neoadjuvant therapy comparing the baseline surgical indication of the MDT to the effective surgery (at least one of: "from mastectomy to breast conservative surgery" OR "from lymph node dissection to sentinel node biopsy").	up to 24 months

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: IRCCS San Raffaele; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Papa Giovanni XXIII Hospital; Humanitas Research Hospital IRCCS, Rozzano-Milan; IEO Foundation

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: February 17, 2026
• First Submitted That Met QC Criteria: February 17, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: breast; neoadjuvant treatment; abemaciclib; oncotype dx; surgical deescalation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; abemaciclib
• Other Study ID Numbers: VIOLET (Boehringer Ingelheim); 2026-525457-37-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No