Post-operative Radiotherapy Omission in Selected Patients With Early Breast Cancer Trial International Validation Experience

Breast Cancer Clinical Trial

— PROSPECTIVE  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06445738
• Other study ID #: BCT 2401
• Status: Not yet recruiting
• Phase: N/A
• Start date: January 1, 2025
• Est. completion date: January 1, 2039

Study information

• Verified date: June 2024
• Source: Breast Cancer Trials, Australia and New Zealand
• Contact: Heath Badger
• Phone: +61 2 4925 5239
• Email: heath.badger[@]bctrials.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1400
• Est. completion date: January 1, 2039
• Est. primary completion date: January 1, 2032
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 50 Years and older

Eligibility

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. In good health and suitable for prolonged follow up with a life expectancy of at least 10 years; willing to be followed 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. Pathology material from index cancer must be available.

7. Have ECOG performance status 0-2.

8. Participants with Grade 3 cancer and/or HER2-positive cancer must agree to comply with systemic treatment recommendations.

• 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 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 IHC47.

2. Previous ipsilateral in-situ or invasive breast cancer.

3. Participants who have a mastectomy for the index cancer.

4. Lymphovascular invasion.

5. Multifocal/multicentric breast cancer.

6. Distant metastasis at diagnosis.

7. Bilateral breast cancer.

8. Known breast cancer predisposition gene mutation carriers (BRCA 1 or 2, PALB2, CHEK2, ATM, CDK1, p53).

9. Contraindication to MRI scanning.

10. Concurrent illness/conditions which limits life expectancy to 10 years.

11. Inability to give informed consent. 10% staining on IHC47.

2) Previous ipsilateral in-situ or invasive breast cancer. 3) Participants who have a mastectomy for the index cancer. 4) Lymphovascular invasion. 5) Multifocal/multicentric breast cancer. 6) Distant metastasis at diagnosis. 7) Bilateral breast cancer. 8) Known breast cancer predisposition gene mutation carriers (BRCA 1 or 2, PALB2, CHEK2, ATM, CDK1, p53).

9) Contraindication to MRI scanning. 10) Concurrent illness/conditions which limits life expectancy to 10 years. 11) 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 (see Section 9.5.2). Participants not fulfilling any one of the following criterial will be allocated to Arm B:

1. Female participants = 50 years old with histologically* confirmed ER-positive and/or HER2-positive, unifocal**, unilateral invasive breast cancer.

2. Has nil/minimal or mild parenchymal enhancement on pre-operative MRI.

3. Breast conserving surgery with invasive primary tumour (including any surrounding DCIS) = 20 mm.

4. 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 all breast tissue from the subcutaneous tissue or pectoralis fascia respectively was removed and radial margins are = 2 mm for invasive cancer and DCIS.

5. pN0 (pN0 i+ is eligible for inclusion) by sentinel node biopsy and/or axillary dissection.

6. Absence of lymphovascular invasion and extensive intraductal component.

7. Have no additional BIRADS 3+ lesions not shown to be benign on pre-operative or surgical biopsy.

8. Participants must be allocated within 8 weeks after final breast surgery.

• 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

• 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 histology

• All foci must have the same hormone (ER and PR) and HER2 status. In relation to Allocation Criteria #3: 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').

Allocation: Arm B - Standard Treatment

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 parenchymal enhancement on pre-operative MRI.

2. Has a biopsy-proven malignant occult lesion (mOL) identified on MRI.

3. Suspicious lesion identified on CEM but not on MRI and confirmed on investigation to be a malignant lesion.

4. Surgical pathology does not meet the inclusion criteria.

5. Clinical team meeting determination that RT be recommended.

6. Participant chooses to have RT despite being eligible for RT omission.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Cancer Female
• Breast Neoplasms

Intervention

Radiation:
• Arm A: Radiotherapy Omission
Omission of radiotherapy based on pre-surgical MRI and pathology findings at surgery.

Other:
• Arm B: Standard Treatment
Ineligible for RT omission on study; includes management of MRI-detected lesions.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Breast Cancer Trials, Australia and New Zealand

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	PRO: Perception of risk of recurrence	To determine differences over time in perception of risk of recurrence between Arm A and Arm B in the breast and elsewhere in the body measured by 2 items adapted from Abbott et al.	From allocation, to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery.
Other	PRO: difference over time in QALYs	To determine difference over time in QALYs between Arm A and Arm B measured by the EQ-5D-5L. A higher score means more problems with health.	From registration to allocation, 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
Other	PRO: Difference in decision regret	To determine difference in decision regret between Arm A and Arm B measured by the Decision Regret Scale (minimum score=1, maximum score=5; higher score indicates more regret).	From registration to allocation, 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
Other	PRO: Overall mental health and differences over time in depression.	To determine 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 a greater symptom burden.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery.
Other	PRO: Overall mental health and differences over time in anxiety	To determine 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 a greater symptom burden.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery.
Other	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
Other	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
Other	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
Other	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.	At the time of the pre-operative MRI
Other	Health Economics: The impact of the PROSPECTIVE model of care on QALYs	Differences in treatment-related morbidity, as measured by QALYs (from the EQ-5D-5L).	60-months post-surgery
Other	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
Other	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
Primary	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 patients with favourable clinico-pathological features on MRI and unequivocally unifocal breast cancer treated with wide local excision but no adjuvant radiotherapy	Median of 5 years follow up (when 300th low risk patient in Arm A reaches 5 years follow up)
Primary	Ipsilateral Invasive Recurrence Rate (IIRR) in all patients omitting RT at a median of 5 years follow up	To determine the ipsilateral invasive recurrence rate (IIRR) in patients allocated to omit radiotherapy	Median of 5 years follow up
Secondary	Ipsilateral Invasive Recurrence Rate (IIRR) in all patients omitting RT at a median of 10 years follow up	To determine the ipsilateral invasive recurrence rate (IIRR) in patients allocated to omit radiotherapy	Median of 10 years follow up
Secondary	IIRR in higher risk patients omitting RT and the total cohort omitting RT	To determine the ipsilateral invasive recurrence rate (IIRR) in higher risk participants and the total cohort omitting RT.	Median of 5 years follow up
Secondary	IIRR in the breast at 5 and 10 years in the entire cohort undergoing pre-operative MRI and ineligible for RT omission	To determine the ipsilateral invasive recurrence rate (IIRR) in the breast at 5 and 10 years in the entire cohort undergoing preoperative MRI and found to be ineligible for RT omission after BCS (Arm B).	Median of 5 and 10 years follow up.
Secondary	IIR in the breast at 5 and 10 years in the entire cohort undergoing pre-operative MRI	To determine the ipsilateral invasive recurrence rate (IIRR) in the breast at 5 and 10 years in the entire cohort undergoing preoperative MRI (Arms A + B).	Median of 5 and 10 years follow up
Secondary	Ipsilateral DCIS recurrence rate in the entire cohort	To determine the ipsilateral DCIS recurrence rate in the entire cohort undergoing pre-operative MRI (Arms A + B).	Median of 5 and 10 years follow up.
Secondary	Ipsilateral DCIS and invasive recurrence rate in all cohorts separately and combined	Ipsilateral DCIS and invasive recurrence rate in all cohorts separately and combined	Median of 5 and 10 years follow up
Secondary	Regional recurrence rate in all participants	To determine the regional recurrence rate in the entire cohort undergoing preoperative MRI (Arms A + B).	Median of 5 and 10 years follow up
Secondary	Distant recurrence rate in all participants	To determine the distant recurrence rate in the entire cohort undergoing preoperative MRI (Arms A + B).	Median of 5 and 10 years follow up
Secondary	Contralateral DCIS and invasive breast cancer in each arm separately, and combined	To determine the contralateral DCIS and invasive breast cancer in Arm A, Arm B, and the total cohort (Arms A + B)	Median of 5 and 10 years follow up
Secondary	Breast cancer specific survival rate in all groups separately and combined	To determine the breast cancer specific survival rate in all groups separately and combined	Median of 5 and 10 years follow up
Secondary	Overall survival rate	To determine the overall survival rate in all groups separately and combined	Median of 5 and 10 years follow up
Secondary	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
Secondary	PRO: HRQoL (functional and aesthetic outcomes)	To determine the difference in HRQoL (functional and aesthetic outcomes) between Arm A and Arm B measured by the Breast Cancer Treatment Outcomes Scale (BCTOS). A higher score indicates greater morbidity.	24 months post-surgery
Secondary	PRO: HRQoL (fatigue, body image, financial toxicity)	To determine the difference in HRQoL (fatigue, body image, financial toxicity) between Arm A and Arm B measured by the EORTC ILXX measure (custom measure for this protocol). A higher score indicates greater fatigue, poorer body image and greater financial toxicity.	24 months post-surgery
Secondary	PRO: Difference over time in FCR	To determine the difference over time in FCR between Arm A and Arm B measured by the FCRI-SF. A higher score indicates a greater fear of recurrence.	From allocation to 3-, 6-, 12-, 24- and 60 months median follow up post-surgery
Secondary	PRO: Difference over time in HRQoL (functional and aesthetic outcomes)	To determine the difference over time in HRQoL (functional and aesthetic outcomes), between Arm A and Arm B measured by the BCTOS. A higher BCTOS score indicates greater morbidity.	From allocation to 6-, 12-, 24- and 60 months median follow up post-surgery
Secondary	PRO: Difference over time in HRQoL (ffatigue, body image, financial toxicity)	To determine the difference over time in HRQoL (fatigue, body image, financial toxicity), between Arm A and Arm B measured by the EORTC ILXX measure (custom measure for this protocol). A higher score indicates greater fatigue, poorer body image and greater financial toxicity.	From allocation to 6-, 12-, 24- and 60 months median follow up post-surgery
Secondary	PRO: Differences in Quality of Life Years (QALYs)	Differences in QALYs between Arm A and Arm B measured by the EQ-5D-5L	24 months post-surgery