Clinical Trials /

EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer

NCT02889874

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

N/A

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: ANZ1601/BIG 16-02
  • SECONDARY ID: 2016-003527-33
  • NCT ID: NCT02889874

Conditions

  • Early Stage Breast Carcinoma

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
A: Radiation Therapy & endocrine therapyNo InterventionPatients randomized to Arm A will receive standard radiation therapy and adjuvant endocrine therapy (standard of care).
    B: No Radiation Therapy (ET only)ExperimentalPatients randomized to Arm B will not receive radiation therapy (omission of radiation therapy) and receive adjuvant endocrine therapy only.

      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 ≤6 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.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:50 Years
      Eligible Gender:Female
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Local recurrence rate after breast conserving surgery
      Time Frame:10 years
      Safety Issue:
      Description: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.

      Secondary Outcome Measures

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

      Details

      Phase:N/A
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Breast Cancer Trials, Australia and New Zealand

      Trial Keywords

      • Radiation therapy
      • omission
      • non-inferiority
      • breast cancer

      Last Updated

      April 17, 2018