Clinical trial NCT06445738: Post-operative Radiotherapy Omission in Selected Patients With Early Breast Cancer Trial International VErsion (PROSPECTIVE)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Breast Cancer
Breast Cancer Female
Keywords: Omission of radiotherapy
Magnetic Resonance Imaging (MRI)
Lead sponsor: Breast Cancer Trials, Australia and New Zealand
Sponsor class: OTHER
First posted: 2024-06-06
Enrollment: 1400
Sex: FEMALE
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A two-arm, non-randomised, prospective, multicentre study using MRI findings and pathology features to select patients with early breast cancer for omission of post-operative radiotherapy.
Primary purpose: OTHER

Brief summary: 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.

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.

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.

Primary outcomes:
measure: Ipsilateral Invasive Recurrence Rate (IIRR) in low-risk patients omitting RT at a median of 5 years follow up
timeFrame: Median of 5 years follow up (when 300th low risk patient in Arm A reaches 5 years follow up)
Secondary outcomes:
measure: Ipsilateral Invasive Recurrence Rate (IIRR) in all participants omitting RT at a median of 10 years follow up after surgery.
timeFrame: Median of 10 years follow up after surgery.
measure: IIRR in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.
timeFrame: Median of 5 years and 10 years follow up after surgery.
measure: Ipsilateral DCIS recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: The combined ipsilateral DCIS and invasive recurrence rate (IRR) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: Regional recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: Distant recurrence rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B..
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: Contralateral DCIS and invasive breast cancer rate in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: Breast cancer specific survival (BCSS) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: Overall Survival (OS) in participants in Arm A1, Arm A2, Arm A, Arm B, and Arms A+B.
timeFrame: Median of 5 and 10 years follow up after surgery.
measure: PRO: Fear of Cancer Recurrence
timeFrame: Median 24 months post-surgery
measure: PRO: Levels of FCR and perception of risk of recurrence in Arm A over time.
timeFrame: At median of 24 months post-surgery
measure: PRO: Difference in FCR and perception of risk of recurrence between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
measure: PRO: Perception of risk of recurrence in Arm A and between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
measure: PRO: Health Related Quality of Life (HRQoL) (functional and aesthetic outcomes, fatigue, body image, financial toxicity) between Arm A and Arm B.
timeFrame: At a median of 24 months post-surgery.
measure: PRO: Health Related Quality of Life (HRQoL) (functional and aesthetic outcomes, fatigue, body image, financial toxicity) in Arm A
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
measure: PRO: Difference over time in HRQoL (functional and aesthetic outcomes, fatigue, body image, financial toxicity) between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
measure: PRO: Quality of Life Years (QALYs) between Arms A and Arm B.
timeFrame: At a median of 24 months follow up post-surgery.
measure: PRO: Difference in QALYs over time between Arm A and Arm B.
timeFrame: From registration to allocation, 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery..
measure: PRO: Difference in Decision Regret between Arm A and Arm B.
timeFrame: At median of 24 months follow up post-surgery.
measure: PRO: Decision Regret in Arm A.
timeFrame: At median 24 months of follow-up post-surgery.
measure: PRO: Overall mental health and depression over time between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
measure: PRO: Overall mental health and differences over time in anxiety in Arm A.
timeFrame: At 24 months median follow-up post-surgery.
measure: PRO: Overall mental health (depression) over time between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
measure: PRO: Overall mental health (anxiety) over time between Arm A and Arm B.
timeFrame: From allocation to 3-, 6-, 12-, 24- and 60 months median follow-up post-surgery.
Other outcomes:
measure: ET: Oncologic outcomes in relation to intensity of endocrine therapy (ET)
timeFrame: Median of 5 and 10 years follow up
measure: Endocrine Therapy: Adherence to ET
timeFrame: Measured at a median of 6-, 24- and 60- months follow-up post-surgery.
measure: Radiology: Outcomes of MRI
timeFrame: At the time of the pre-operative MRI
measure: Radiology: Occult lesion and malignant occult lesion detection rate
timeFrame: At the time of the pre-operative MRI
measure: Radiology: Frequency and nature of occult lesions from Contrast Enhanced Mammography (CEM)
timeFrame: At the time of the pre-operative MRI
measure: Health Economics: The impact of the PROSPECTIVE model of care on costs and QALYs
timeFrame: 60-months post-surgery
measure: Translational Research: Identify potential biomarkers of response and investigate tumour dynamics to identify patients in whom adjuvant therapy may be safely omitted.
timeFrame: At the time of diagnosis
measure: Translational Research: Identify potential biomarkers of response and investigate tumour dynamics to identify patients in whom adjuvant therapy may be safely omitted.
timeFrame: At the time of surgery for recurrence
Locations:
city: Camperdown
country: Australia
facility: The Chris O'Brien Lifehouse
state: New South Wales
city: Gateshead
country: Australia
facility: Lake Macquarie Private Hospital
state: New South Wales
city: North Sydney
country: Australia
facility: Mater Hospital, Sydney
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Cancer Centre (MMC Moorabbin)
state: Victoria
city: Melbourne
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
Study officials:
affiliation: Melbourne Health
name: Bruce Mann, MD
role: STUDY_CHAIR
affiliation: Peter MacCallum Cancer Centre - Moorrabin
name: Steven David, MD
role: STUDY_CHAIR
affiliation: Baylor College of Medicine
name: Alastair Thompson, MD
role: STUDY_CHAIR
References: