Omitting post-operative radiotherapy for selected early breast cancer patients based on MRI

A Two-arm, Non-randomised, Prospective, Multicentre Study Using Magnetic Resonance Imaging (MRI) Findings and Pathology Features to Select Patients With Early Breast Cancer for Omission of Post-operative Radiotherapy

This trial will test whether women aged 50 and older with early ER-positive and/or HER2-positive breast cancer can safely skip radiotherapy after surgery when preoperative MRI and pathology show favorable features.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 1400 (estimated)
• Ages: 50 Years and up
• Sex: Female
• Sponsor: Breast Cancer Trials, Australia and New Zealand (Academic / other)
• Drugs / interventions: radiation
• Locations: 9 sites (San Francisco, California and 8 other locations)
• Trial ID: NCT06445738 on ClinicalTrials.gov

What this trial studies

PROSPECTIVE uses preoperative breast MRI combined with pathological features to identify patients with unifocal, unilateral early breast cancer who might safely omit adjuvant radiotherapy. Eligible participants meeting the imaging and pathology criteria are allocated to either radiotherapy omission or standard postoperative radiotherapy. The protocol includes long-term follow-up (planned for at least 10 years) to track ipsilateral breast tumor recurrence and other outcomes, and includes health economic and patient-reported components. This international effort builds on supportive results from the earlier ANZ 1002 PROSPECT phase II experience.

Who should consider this trial

Good fit: Women aged 50 or older with histologically confirmed unifocal, unilateral invasive breast cancer that is ER-positive and/or HER2-positive, ECOG 0-2, with life expectancy ≥10 years who can undergo preoperative MRI and timely surgery are the intended candidates.

Not a fit: Patients with multifocal or bilateral disease, high-risk pathological features or unfavorable MRI findings, poor performance status, or inability to complete required MRI or follow-up are unlikely to benefit from radiotherapy omission.

Why it matters

Potential benefit: If successful, many patients could avoid radiotherapy, lowering treatment side effects, inconvenience, and overall health-care costs.

How similar studies have performed: A prior ANZ 1002 PROSPECT phase II study produced supportive results suggesting MRI plus pathology can identify a low-risk group, but broad international validation is still limited.

Eligibility criteria

Inclusion Criteria:

For inclusion in the study at Registration, participants must fulfil all of the following criteria:

1. Has provided written, informed consent to participate in the study.
2. Female participants ≥ 50 years old with histologically\* confirmed ER-positive and/or HER2-positive invasive breast cancer.
3. Has a life expectancy of at least 10 years and suitable for prolonged follow up for 10 years.
4. Breast imaging indicating unifocal, unilateral breast cancer must have been performed before pre-registration.
5. Willing/able to have surgery within 8 weeks of registration or pre-operative MRI, whichever occurs later.
6. Have ECOG performance status 0-2.

   * Oestrogen receptor and progesterone receptor status of invasive cancer will be assessed by immunohistochemistry on the diagnostic core biopsy specimen. The IHC results will be reported as percentage of nuclei stained and a score of intensity from negative, weak, intermediate or high staining

HER2 neu status will be assessed by immunohistochemistry and will be scored as follows46:

* 0 or 1+ (HER2 negative): No staining or membrane staining that is incomplete and is faint/barely perceptible and in ≤ 10% of tumour cells (0); or incomplete membrane staining that is faint/barely perceptible and in \> 10% of tumour cells (1+).
* 2+ (equivocal): weak to moderate complete membrane staining observed in \> 10% of tumour cells. Must order reflex test (same specimen using ISH) or order a new test (new specimen if available using HIS or ISH).
* 3+ (HER2 positive): Circumferential membrane staining that is complete, intense and in \> 10% of tumour cells.

Exclusion Criteria:

Any one of the following at Registration is regarded as a criterion for exclusion from the study:

1. Triple negative breast cancer (ER-negative and PR-negative and HER2-negative) where ER and PR positivity is defined as ≥ 10% staining on IHC.
2. Previous invasive breast cancer and/or DCIS in either breast.
3. Prior RT to the breast or chest.
4. Participants who plan to have a mastectomy for the index cancer.
5. Lymphovascular invasion (LVI) reported on diagnostic core biopsy.
6. Multifocal/multicentric breast cancer on breast imaging before registration.
7. Distant metastasis at diagnosis.
8. Bilateral breast cancer
9. Known breast cancer predisposition gene mutation carriers (BRCA1, BRCA2, PALB2, CHEK2, ATM, CDK1, p53, BARD1, RAD51C, RAD51D, CDH1, STK11, PTEN).
10. Contraindication to breast MRI scanning.
11. Concurrent illness/conditions which limits life expectancy to 10 years or less.
12. Has moderate or marked BPE in the breast containing the index cancer (where MRI is done before registration).
13. Inability to give informed consent.

Allocation: Arm A - Radiotherapy Omission

In addition to the above criteria, for inclusion in the omission of radiation therapy arm of the study after surgery, participants must fulfil all the following criteria. Participants not fulfilling any one of the following criterial will be allocated to Arm B:

1. Has nil/minimal or mild BPE in the breast containing the index lesion on pre-operative breast MRI.
2. BCS with unifocal\*\*, invasive primary tumour (including any surrounding DCIS) ≤ 20 mm.

   The overall tumour size (including additional foci of DCIS) must remain ≤ 20 mm. The tumour size is defined as the longest distance between the outer most edges of all foci, the space between the two or more foci is included in the overall size: Size = ('Focus A + Focus B + 'the distance between A and B').
3. Radial resection margins must be ≥ 2 mm clear of any invasive cancer and ≥ 2 mm clear of any DCIS. Superficial or deep margins of \< 2 mm for invasive cancer and DCIS are allowed if there is no tumour on ink and all breast tissue from the subcutaneous tissue or pectoralis fascia respectively was removed and radial margins are ≥ 2 mm for invasive cancer and DCIS.
4. pN0 (pN0 i+ is eligible for inclusion) by sentinel node biopsy and/or axillary dissection.
5. Absence of LVI and extensive intraductal component (EIC) on final pathology.
6. The extent of invasive cancer is at least 50% of the total tumour size (invasive cancer + DCIS).
7. Have no additional BIRADS 3+ lesions not shown to be benign on pre-operative or surgical biopsy.
8. Participants with Grade 3 cancer and/or HER2-positive cancer must agree to comply with systemic treatment recommendations.
9. Participants must be allocated to a treatment arm within 8 weeks after final breast surgery.

   * Where histopathology is unable to identify a 'bridge' of tumour tissue joining two or more apparent invasive cancer foci the following will be used to confirm unifocal disease:

     * All foci must be of the same histological subtype
     * All foci must have the same hormone (ER and PR) and HER2 status.

Allocation: Arm B - Standard Treatment (ineligible for RT omission on study; includes management of MRI-detected lesions)

In addition to the above Inclusion Criteria, participants who fulfil one any of the following criteria will receive standard treatment:

1. Has moderate or marked BPE in the breast containing the index lesion on pre-operative breast MRI.
2. Has a biopsy-proven mOL identified on breast MRI.
3. Suspicious lesion identified on CEM but not on MRI and confirmed on investigation to be a DCIS or invasive breast cancer.
4. Surgical pathology does not meet the inclusion criteria. 2mm radial margins are required, as guidelines suggesting "no tumour on ink" relate to those receiving adjuvant RT.
5. Clinical team meeting determination that RT be recommended.
6. Participant chooses to have RT despite being eligible for RT omission.

Where this trial is running

San Francisco, California and 8 other locations

• UCSF Breast Care Center — San Francisco, California, United States (Not_yet_recruiting)
• Baylor St Luke's Medical Centre — Houston, Texas, United States (Not_yet_recruiting)
• The Chris O'Brien Lifehouse — Camperdown, New South Wales, Australia (Not_yet_recruiting)
• Lake Macquarie Private Hospital — Gateshead, New South Wales, Australia (Not_yet_recruiting)
• Mater Hospital, Sydney — North Sydney, New South Wales, Australia (Recruiting)
• Westmead Hospital — Westmead, New South Wales, Australia (Not_yet_recruiting)
• Royal Adelaide Hospital — Adelaide, South Australia, Australia (Not_yet_recruiting)
• Monash Cancer Centre (MMC Moorabbin) — Clayton, Victoria, Australia (Recruiting)
• The Royal Melbourne Hospital — Melbourne, Victoria, Australia (Recruiting)

Study contacts

• Study coordinator: Heath Badger

Conditions Breast Cancer; Breast Cancer Female; Omission of radiotherapy; Magnetic Resonance Imaging