Post-operative Radiotherapy Omission in Selected Patients With Early Breast Cancer Trial International VErsion (PROSPECTIVE) (PROSPECTIVE)

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

The PROSPECTIVE trial aims to find out if using the results of Magnetic Resonance Imaging (MRI) for early breast cancer can select people to not have radiotherapy and still have a low chance of the cancer coming back after surgery.

The main question it aims to answer is:

* Will cancer come back in the same breast as the original cancer in patients who have surgery for their breast cancer, but who don't have radiotherapy afterwards because the results of an MRI before surgery showed favourable characteristics for not having radiotherapy.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Breast Cancer Female
• Intervention / Treatment: Radiation: Arm A: Radiotherapy Omission; Other: Arm B: Standard Treatment

Detailed Description

Breast cancer is the most common serious malignancy in women and most patients are suitable for therapy involving surgery and adjuvant radiotherapy (RT). For most patients, there is a lack of evidence that breast conserving surgery without adjuvant RT is safe and therefore patients bear the costs, inconvenience and morbidity of RT. Prior attempts to identify large subsets of patients for whom RT can be safely omitted based on clinicopathological features of the index cancer have had limited success, and so RT is currently omitted only in some women over 65 or 70 with small low risk cancers. Identification of a much larger subset of patients in whom adjuvant RT could be safely omitted would be hugely significant, not only to the patients, but to the entire health system.

The ANZ 1002 PROSPECT study was a two-arm phase II study that used breast MRI findings and pathological features to identify a group of patients with low risk early breast cancer in whom RT may be safely omitted. The findings at the primary strongly support the hypothesis and suggest that the combination of preoperative MRI and pathological features can identify a substantial group of early breast cancer patients in whom adjuvant RT can be safely omitted.

A Health Economic analysis of PROSPECT found that the avoided costs of RT and its potential side effects is likely to substantially outweigh the extra cost of MRI scans and associated investigations. Parallel cross-sectional studies assessing Fear of Cancer Recurrence (FCR) and Health Related Quality of Life (HRQoL) in patients taking part in PROSPECT who either did or did not receive RT and a control group found a substantially lower FCR in PROSPECT patients who omitted RT as well as improved HRQoL.

The majority of screened and eligible patients (427/443 and 193/201, respectively) for PROSPECT were recruited from two Australian sites. Before the PROSPECT approach can be widely adopted, the findings need to be replicated in a multicentre, international study. In addition, patient reported outcomes and health economic assessments need to be performed prospectively and longitudinally.

PROSPECTIVE is the follow-up to PROSPECT which will address these issues, and also include translational research aspects to further study the natural history and outcomes of this group of lower risk early breast cancers.

• Study Type: Interventional
• Enrollment (Estimated): 1400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Heath Badger; Phone Number: +61 2 4925 5239; Email: heath.badger@bctrials.org.au

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Not yet recruiting
      • The Chris O'Brien Lifehouse
      • Principal Investigator: Sanjay Warrier, A/Prof
    • Gateshead, New South Wales, Australia, 2290
      • Not yet recruiting
      • Lake Macquarie Private Hospital
      • Principal Investigator: Shanta Velaiutham, Dr
    • North Sydney, New South Wales, Australia, 2060
      • Recruiting
      • Mater Hospital, Sydney
      • Principal Investigator: Andrew Spillane, Prof
    • Westmead, New South Wales, Australia, 2145
      • Not yet recruiting
      • Westmead Hospital
      • Principal Investigator: Elisabeth Elder, Dr
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Not yet recruiting
      • Royal Adelaide Hospital
      • Principal Investigator: Janne Bingham, Dr
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Monash Cancer Centre (MMC Moorabbin)
      • Principal Investigator: Corinne Wei Leng Ooi, Dr
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • The Royal Melbourne Hospital
      • Principal Investigator: Bruce Mann, Prof
• United States
  • California
    • San Francisco, California, United States, 94158
      • Not yet recruiting
      • UCSF Breast Care Center
      • Contact: Michael Alvarado, Prof; Phone Number: +1 (415) 353-7070; Email: michael.alvarado@ucsf.edu
      • Principal Investigator: Michael Alvarado, Prof
  • Texas
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • Baylor St Luke's Medical Centre
      • Contact: Alastair Thompson, Prof; Phone Number: +1 (713) 798 2901; Email: alastair.thompson@bcm.edu
      • Principal Investigator: Alastair Thompson, Prof

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiotherapy Omission; Participants with nil, minimal or mild parenchymal enhancement on pre-operative MRI whose pathology meets inclusion/exclusion requirements for omission of post-operative radiotherapy will be allocated to Arm A, unless the participant prefers to receive Standard Treatment (Arm B) or following clinical team recommendation. Arm A participants will be divided into 2 groups: Arm A1: Grade 1 or 2/HER2 negative ("low risk"); Arm A2: Grade 3 and/or HER2 positive ("high risk")	Radiation: Arm A: Radiotherapy Omission; Omission of radiotherapy based on pre-surgical MRI and pathology findings at surgery.; Other Names: A1: Grade 1 or 2/HER2 negative; A2: Grade 3 and/or HER2 positive
Active Comparator: Standard Treatment; Participants who are found to be ineligible for RT omission on study; includes management of MRI-detected lesions. Participants with any of: Moderate or marked parenchymal enhancement on pre-operative MRI; A malignant occult lesion identified on MRI; or; Pathology that does not meet inclusion/exclusion criteria will receive standard multidisciplinary team recommendations to guide treatment. Participants may also be included in Arm B due to their own preference or following clinical team recommendation.	Other: Arm B: Standard Treatment; Ineligible for RT omission on study; includes management of MRI-detected lesions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ipsilateral Invasive Recurrence Rate (IIRR) in low-risk patients omitting RT at a median of 5 years follow up	To determine the ipsilateral invasive recurrence rate (IIRR) in lower risk patients with unequivocally unifocal breast cancer and on breast MRI and favourable clinico-pathological features.	Median of 5 years follow up (when 300th low risk patient in Arm A reaches 5 years follow up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PRO: Fear of Cancer Recurrence	To determine the difference in Fear of cancer recurrence (FCR) between Arm A and Arm B measured by the Fear of Cancer Recurrence Inventory Short Form (FCRI-SF). A higher score indicates a greater fear of recurrence.	Median 24 months post-surgery
Ipsilateral Invasive Recurrence Rate (IIRR) in all participants omitting RT at a median of 10 years follow up after surgery.	To determine the ipsilateral invasive recurrence rate (IIRR) in patients allocated to omit radiotherapy (Arm A1).	Median of 10 years follow up after surgery.
IIRR in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	To determine the ipsilateral invasive recurrence rate (IIRR) in participants in Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 years and 10 years follow up after surgery.
Ipsilateral DCIS recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	To determine the ipsilateral DCIS rate in the breast in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 and 10 years follow up after surgery.
The combined ipsilateral DCIS and invasive recurrence rate (IRR) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	To determine the combined ipsilateral DCIS and invasive recurrence rate (IRR) in the breast in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 and 10 years follow up after surgery.
Regional recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	To determine the regional recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 and 10 years follow up after surgery.
Distant recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B..	To determine the distant recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 and 10 years follow up after surgery.
Contralateral DCIS and invasive breast cancer rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B	To determine the contralateral DCIS and invasive breast cancer rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	Median of 5 and 10 years follow up after surgery.
Breast cancer specific survival (BCSS) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B	BCCS rate defined as the percentage of people who have not died from breast cancer.	Median of 5 and 10 years follow up after surgery.
Overall Survival (OS) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.	OS rate defined as the percentage of people alive.	Median of 5 and 10 years follow up after surgery.
PRO: Levels of FCR and perception of risk of recurrence in Arm A over time.	To determine the difference in levels of FCR and perception of risk of recurrence in Arm A measured by the Fear of Cancer Recurrence Inventory - Short Form and 2 items adapted from Abbott et al. A higher score indicates greater fear of recurrence and greater risk perception.	At median of 24 months post-surgery
PRO: Difference in FCR and perception of risk of recurrence between Arm A and Arm B.	To determine the difference over time in FCR and perception of risk of recurrence between Arm A and Arm B over time as measured by the FCRI-SF and 2 items adapted from Abbott et al. A higher score indicates greater fear of recurrence and greater risk perception.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
PRO: Perception of risk of recurrence in Arm A and between Arm A and Arm B.	To determine the difference in perceptions of risk of recurrence in the breast and elsewhere in the body measured by 2 items adapted from Abbott et al. A higher score indicates greater risk perception.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
PRO: Health Related Quality of Life (HRQoL) (functional and aesthetic outcomes, fatigue, body image, financial toxicity) between Arm A and Arm B.	To determine the difference in breast-specific symptoms, cosmetic status, arm- and shoulder functional status measured by the Breast Cancer Treatment Outcomes Scale (BCTOS); and fatigue, body image, financial toxicity measured by the EORTC IL353. A higher score indicates greater morbidity, greater fatigue; greater financial toxicity; poorer body image.	At a median of 24 months post-surgery.
PRO: Health Related Quality of Life (HRQoL) (functional and aesthetic outcomes, fatigue, body image, financial toxicity) in Arm A	To determine the HRQoL (functional and aesthetic outcomes, fatigue, body image, financial toxicity), in Arm A measured by the BCTOS (breast-specific symptoms, cosmetic status, arm- and shoulder functional status) EORTC IL353 measure (custom measure for this protocol) (fatigue, body image, financial toxicity). A higher score indicates greater fatigue, poorer body image and greater financial toxicity.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
PRO: Difference over time in HRQoL (functional and aesthetic outcomes, fatigue, body image, financial toxicity) between Arm A and Arm B.	To determine the difference in breast-specific symptoms, cosmetic status, arm- and shoulder functional status measured by the BCTOS; and fatigue, body image, financial toxicity measured by the EORTC IL353between Arm A and Arm B.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
PRO: Quality of Life Years (QALYs) between Arms A and Arm B.	To determine the Quality of Life Years (QALYs) between Arms A and Arm B measured by the EQ-5D-5L. A high score indicates more problems.	At a median of 24 months follow up post-surgery.
PRO: Difference in QALYs over time between Arm A and Arm B.	To determine the Quality of Life Years (QALYs) between Arms A and Arm B over time measured by the EQ-5D-5L. A high score indicates more problems.	From registration to allocation, 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery..
PRO: Difference in Decision Regret between Arm A and Arm B.	To determine the difference in decision regret between Arm A and Arm B measured by Decision Regret Scale. A higher score indicates more regret.	At median of 24 months follow up post-surgery.
PRO: Decision Regret in Arm A.	To determine decision regret in Arm A measured by Decision Regret Scale. A higher score indicates more regret.	At median 24 months of follow-up post-surgery.
PRO: Overall mental health and depression over time between Arm A and Arm B.	To determine the overall mental health and differences over time in depression between Arm A and Arm B. Measured by the Patient Health Questionnaire-2. A higher score indicates and greater symptom burden.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
PRO: Overall mental health and differences over time in anxiety in Arm A.	To determine the overall mental health and differences over time in anxiety in Arm A, measured by the Generalized Anxiety Disorder-2. A higher score indicates a higher symptom burden.	At 24 months median follow-up post-surgery.
PRO: Overall mental health (depression) over time between Arm A and Arm B.	To determine the overall mental health and differences over time in depression between Arm A and Arm B. Measured by the Patient Health Questionnaire-2. A higher score indicates and greater symptom burden.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
PRO: Overall mental health (anxiety) over time between Arm A and Arm B.	To determine the overall mental health and differences over time in anxiety between Arm A and Arm B. Measured by the Generalized Anxiety Disorder-2. A higher score indicates and greater symptom burden.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ET: Oncologic outcomes in relation to intensity of endocrine therapy (ET)	To analyse oncological outcomes in relation to the intensity of endocrine therapy (ET) (no ET, less than 2 years ET, 2-5 years ET, more than 5 years ET).	Median of 5 and 10 years follow up
Radiology: Occult lesion and malignant occult lesion detection rate	To number of occult lesions and malignant occult lesions detected on pre-operative MRI per institution	At the time of the pre-operative MRI
Radiology: Outcomes of MRI	Outcomes of MRI in those patients who have MRI post-registration measured by BPR, occult lesion rate, biopsy approach, result of biopsy, malignant occult lesion rate.	At the time of the pre-operative MRI
Translational Research: Identify potential biomarkers of response and investigate tumour dynamics to identify patients in whom adjuvant therapy may be safely omitted.	By sequencing and analysis of index tumours.	At the time of diagnosis
Translational Research: Identify potential biomarkers of response and investigate tumour dynamics to identify patients in whom adjuvant therapy may be safely omitted.	By sequencing and analysis of recurrent tumours.	At the time of surgery for recurrence
Endocrine Therapy: Adherence to ET	ET side effects as measured with the FACT-ES.	Measured at a median of 6-, 24- and 60- months follow-up post-surgery.
Radiology: Frequency and nature of occult lesions from Contrast Enhanced Mammography (CEM)	Measured by the frequency of occult lesions on CEM in patients undergoing CEM in addition to MRI and comparison of CEM and MRI findings.	At the time of the pre-operative MRI
Health Economics: The impact of the PROSPECTIVE model of care on costs and QALYs	Health economic impact of including preoperative MRI and post-operative modification of adjuvant therapy in early breast cancer management in patients who have not had an MRI or CEM before PROSPECTIVE registration, as measured by QALYs (from the EQ-5D-5L).	60-months post-surgery

Collaborators and Investigators

• Sponsor: Breast Cancer Trials, Australia and New Zealand
• Investigators: Study Chair: Alastair Thompson, MD, Baylor College of Medicine; Study Chair: Bruce Mann, MD, Melbourne Health; Study Chair: Steven David, MD, Peter MacCallum Cancer Centre - Moorrabin

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2025
• Primary Completion (Estimated): June 1, 2032
• Study Completion (Estimated): June 1, 2039

Study Registration Dates

• First Submitted: May 24, 2024
• First Submitted That Met QC Criteria: June 4, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging (MRI); Omission of radiotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: BCT 2401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised Individual Patient Data (IPD) collected during the trial.
• IPD Sharing Time Frame: Data will be made available for request after publication of the main/final study results; no end date.
• IPD Sharing Access Criteria: Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Applications will be subject to approval by Breast Cancer Trials concept@bctrials.org.au (refer to BCT Data Sharing Guidelines).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No