EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer (EXPERT)

• ClinicalTrials.gov Identifier: NCT02889874
• Recruitment Status: Recruiting
• First Posted: September 7, 2016
• Last Update Posted: August 24, 2020
• Sponsor: Breast Cancer Trials, Australia and New Zealand
• Collaborators: Breast International Group; International Breast Cancer Study Group
• Information provided by (Responsible Party): Breast Cancer Trials, Australia and New Zealand

Tracking Information

• First Submitted Date: August 25, 2016
• First Posted Date: September 7, 2016
• Last Update Posted Date: August 24, 2020
• Actual Study Start Date: August 21, 2017
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 8, 2018)

Local recurrence rate after breast conserving surgery [ Time Frame: 10 years ]

The time from randomisation to the date of local recurrence (LR) as a site of first recurrence.

Original Primary Outcome Measures (submitted: August 31, 2016)

Local recurrence rate after breast conserving surgery [ Time Frame: 10 years ]

To determine if omission of RT is not inferior to RT in terms of local recurrence rate after breast conserving surgery in patients with stage I, biologically low-risk luminal-A subtype early breast cancer who receive adjuvant endocrine therapy.

Current Secondary Outcome Measures (submitted: October 8, 2018)

• Local-regional recurrence-free interval (LRRFI) [ Time Frame: 10 years ]
  Time from randomisation to the date of local or regional recurrence as a site of first recurrence.
• Distant recurrence-free interval (DRFI) [ Time Frame: 10 years ]
  Time from randomisation to the date of distant recurrence, regardless of occurrence of any intervening local or regional recurrence, contralateral breast cancer or second (non-breast) primary invasive cancer.
• Disease free survival including DCIS (DFS-DCIS) [ Time Frame: 10 years ]
  Time from randomisation to date of first evidence of local (invasive breast carcinoma or DCIS), regional or distanct recurrence; contralateral breast cancer (invasive breast carcinoma or DCIS); second (non-breast) primary invasive cancer; or death.
• Invasive disease free survival (iDFS) [ Time Frame: 10 years ]
  Time from randomisation to date of first evidence of local (invasive breast carcinoma), regional or distanct recurrence; contralateral breast cancer (invasive breast carcinoma); second (non-breast) primary invasive cancer; or death.
• Recurrence-free interval [ Time Frame: 10 years ]
  Time from randomisation to the date of local, regional or distant recurrence as a site of first recurrence.
• Overall survival (OS) [ Time Frame: 10 years ]
  Time from randomisation to date of death from any cause.
• Salvage RT or mastectomy rate [ Time Frame: 10 years ]
  Time from randomisation to the receipt of salvage RT or mastectomy, individually and in combination (one or the other) as a composite endpoint.
• Adverse events for patients [ Time Frame: 5 years ]
  Adverse events during treatment (up to 5 years of endocrine therapy) assessed using NCI CTCAE v4.0.
• Assessment of the impact of endocrine therapy [ Time Frame: 5 years ]
  FACT-ES measure of endocrine symptoms.

Original Secondary Outcome Measures (submitted: August 31, 2016)

• Local-regional recurrence-free interval (LRRFI) [ Time Frame: 10 years ]
• Distant recurrence-free interval (DRFI) [ Time Frame: 10 years ]
• Disease free survival including DCIS (DFS-DCIS) [ Time Frame: 10 years ]
• Invasive disease free survival (iDFS) [ Time Frame: 10 years ]
• Breast cancer specific survival (BCSS) [ Time Frame: 10 years ]
• Overall survival (OS) [ Time Frame: 10 years ]
• Salvage RT or mastectomy rate [ Time Frame: 10 years ]
  each to be assessed individually and in combination as a composite endpoint
• Adverse events for patients [ Time Frame: 5 years ]
  Adverse events during treatment (up to 5 years of endocrine therapy)
• Patient compliance with endocrine therapy [ Time Frame: 5 years ]
  FACT-ES measure
• Patient compliance with endocrine therapy [ Time Frame: 5 years ]
  Morisky Compliance Questionnaire (MMAS-4)

Current Other Pre-specified Outcome Measures (submitted: August 31, 2016)

• Quality of Life: Fear of recurrence [ Time Frame: 5 years ]
  Fear of Cancer Recurrence Inventory
• Quality of Life: Convenience of care [ Time Frame: 5 years ]
  Visual Analogue Scales (convenience and impact of treatment)

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer
• Official Title: A Randomised Phase III Trial of Adjuvant Radiation Therapy Versus Observation Following Breast Conserving Surgery and Endocrine Therapy in Patients With Molecularly Characterised Luminal A Early Breast Cancer
• Brief Summary: This is a randomised, phase III, non-inferiority trial evaluating radiation therapy versus observation following breast conserving surgery and planned endocrine therapy in patients with stage I breast cancer of luminal A subtype defined using the Prosigna (PAM50) Assay.

Detailed Description

Radiation therapy (RT) after breast conserving surgery to improve local control and survival is the current standard of care for patients with early breast cancer. However, breast cancer is a heterogeneous disease, and the absolute benefit of RT in individual patients varies substantially. Thus, a pressing priority in contemporary breast cancer management is to tailor RT utilisation to the individual recurrence risks by identifying patients who are unlikely to benefit from RT, thereby avoiding the morbidity and costs of over-treatment.

It is recognised that selected patients with early breast cancer are unlikely to derive benefits from RT after breast conserving surgery. However, randomised trials have not consistently identified patients who may safely omit RT using conventional clinical-pathologic characteristics.

Breast cancer intrinsic subtypes distinguished by gene expression profiling are shown to be associated with distinct clinical outcomes. There is substantial evidence supporting the clinical validity of multigene assays including the PAM50-based Prosigna Assay that identifies intrinsic subtypes and generates a Risk of Recurrence score (ROR) to quantify individual risks of distant relapse. Multigene assays are increasingly integrated into clinical practice to inform chemotherapy decision, highlighting their substantial practice changing potential in personalising the use of RT for early breast cancer.

A recent analysis of archived tumour specimens of 1,308 patients with early breast cancer has shown significant associations between local recurrence risk and the PAM50-defined intrinsic subtypes and ROR score. EXPERT presents a unique opportunity of clinical and public health importance to optimise personalised local therapy for early breast cancer through precise, individualised quantification of local recurrence risk to identify low-risk patients for whom RT after breast conserving surgery may be safely omitted.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Early Stage Breast Carcinoma

Intervention

Radiation: Omission of radiation therapy

Omission of radiation therapy (adjuvant endocrine therapy only).

Study Arms

• No Intervention: A: Radiation Therapy & endocrine therapy
  Patients randomized to Arm A will receive standard radiation therapy and adjuvant endocrine therapy (standard of care).
• Experimental: B: No Radiation Therapy (ET only)
  Patients randomized to Arm B will not receive radiation therapy (omission of radiation therapy) and receive adjuvant endocrine therapy only.
  Intervention: Radiation: Omission of radiation therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 31, 2016): 1167
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: for registration in the study:

1. Female patients aged ≥ 50 years of any menopausal status.

2. Primary tumour characteristics as assessed by conventional histopathology:

   • Unifocal histologically confirmed invasive breast carcinoma
   • Maximum microscopic size ≤2 cm
   • Grade 1 or 2 histology
   • ER and PR positive in ≥10% of tumour cells in either the biopsy or breast conserving surgical specimen
   • HER2 negative on IHC (score 0 or 1+) or in situ hybridisation (ERBB2-amplification Ratio ERBB2/centromeres <2.0 or mean gene copy number <6). Equivocal IHC score (2+) must be assessed by ISH.
3. Primary tumour must be resected by breast conserving surgery with microscopically negative margins for invasive carcinoma and any associated ductal carcinoma in situ (no cancer cells adjacent to any inked edge/surface of specimen) or re-excision showing no residual disease.
4. Histologically confirmed negative nodal status determined by sentinel node biopsy or axillary dissection. Patients with pN0 (i+) disease are eligible for study participation (malignant cells ≤0.2 mm in regional lymph node(s) detected by hematoxylin-eosin (H&E) stain or IHC, including isolated tumour cells).
5. No evidence of distant metastasis.
6. Eligible for and willing to have adjuvant endocrine therapy.
7. ECOG performance status 0-2.
8. Availability of FFPE tumour block for Prosigna (PAM50) Assay.

For randomization to the study, patients must fulfill all of the following criteria:

1. Primary tumour characteristics as assessed by Prosigna (PAM50) Assay:

• Luminal A intrinsic subtype
• ROR score ≤60

Exclusion Criteria:

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

1. Primary tumour characteristics:

   • Presence of multifocal or multicentric invasive carcinoma or ductal carcinoma in situ;
   • Evidence of clinical or pathologic T4 disease (extension to the chest wall, oedema or ulceration of skin, satellite skin nodules, inflammatory carcinoma);
   • The invasive component of the primary tumour is present as micro-invasion only;
   • Grade 3 histology;
   • Presence of lymphovascular invasion
2. Contra-indication or unwillingness to have adjuvant endocrine therapy.
3. Planned to receive adjuvant chemotherapy or biologic therapy after breast cancer surgery, i.e. any systemic therapy other than endocrine therapy is not permitted. Any therapy unrelated to cancer is permitted at the discretion of investigators.
4. Treated with neoadjuvant endocrine therapy, chemotherapy or biologic therapy prior to breast cancer surgery.
5. Prior breast or thoracic RT for any condition.
6. Pre-operative breast imaging evidence of disease aside from the primary carcinoma resected by breast conserving surgery.
7. Concurrent invasive breast carcinoma or ductal carcinoma in situ (synchronous or metachronous).
8. Prior diagnosis of invasive breast carcinoma or ductal carcinoma in situ in either breast irrespective of disease free interval.

9. A diagnosis of non-breast malignancy <5 years prior to randomisation with the following exceptions:

   • Patients who are diagnosed with carcinoma in situ of cervix, endometrium or colon; melanoma in situ; and basal or squamous cell carcinoma of the skin at any time prior to randomisation are not excluded from study participation.
   • Patients who are diagnosed with other non-breast malignancy ≥5 years prior to randomisation and without evidence of disease recurrence are not excluded from study participation.
10. Significant comorbidity precluding definitive RT for breast cancer (e.g. cardiovascular or pulmonary disease, scleroderma, systemic lupus erythematosus).
11. Life expectancy <10 years.
12. Documented mutation of BRCA1, BRCA2 or TP53, or at high genetic risk of breast cancer.
13. Pregnant or lactating patients.
14. Inability to be registered to the study ≤8 weeks after the last surgical procedure for breast cancer.
15. Inability to commence RT (if randomised to receive RT) no later than 12 weeks from the last surgical procedure for breast cancer.
16. Inability to provide written informed consent.
17. Psychiatric, addictive, or any disorder that precludes compliance with protocol requirements.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Heath Badger; +61 2 4925 5239; expert@bctrials.org.au

Contact: Akiko Fong; +61 2 4925 5230; expert@bctrials.org.au

• Listed Location Countries: Australia, New Zealand, Taiwan

Administrative Information

• NCT Number: NCT02889874
• Other Study ID Numbers: ANZ1601/BIG 16-02; 2016-003527-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: to be defined.

• Responsible Party: Breast Cancer Trials, Australia and New Zealand
• Study Sponsor: Breast Cancer Trials, Australia and New Zealand

Collaborators

• Breast International Group
• International Breast Cancer Study Group

Investigators

• Study Director: Heath Badger; Breast Cancer Trials, Australia and New Zealand
• Study Chair: Boon H Chua, Prof; Prince of Wales Hospital

• PRS Account: Breast Cancer Trials, Australia and New Zealand
• Verification Date: August 2020